CA2111214A1 - Composition and treatment with biologically active peptides having c-terminal substitutions - Google Patents

Abstract

A C-terminal substituted peptide or protein of formula (I), wherein X is a biologically active amphiphilic ion channel-forming peptide or protein. T is selected from the group consisting of: (a) O-R, wherein R is a substituted or unsubstituted aliphatic, aromatic or aralkyl group having from 1 to 10 carbon atoms; (b) NH-NH2; (c) NH-OH; and (d) .alpha., wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein group (i) is a hydroxy-substituted aliphatic, aromatic or aralkyl group having no more than 10 carbon atoms, and group (ii) is an amino-substituted aliphatic, aromatic, aralkyl, or alkylaromatic group, preferably having no more than 10 carbon atoms, and at least one of R' and R" is group (i) or group (ii).

Description

Q ~ 1~
~W O 92~22317 PC~r/USg2/04603 COMPOSITION AND TREATMIENT WITH BIOLOGICALLY
ACTIVE PEPTIDES HAVING C-TERMINAL SUBSTITUTIONS
______________ _________ ____ ______ _____ __ _ This appli~ation is a continuation-in-part of application Serial No. 713,716, filed June 12, 1991.
This invention relates to biologicall~ acti~e peptides and proteins, and more particularly to compositi.ons ~nd uses involving biologically active peptides having C-terminal sub~titutions.
In accordance ~ith an a~pect of the present invention, there is provided a composition compri.siny a ~-te~in23 substituted peptide or protein of the formula:
O
il X-C-T, wherein X i~ a biolo~ically active ~mphiphii.ic p~ptide or protein. The peptide or protein is an ion channel-forming peptide or prote~n. T is select~d from the group con~isting of:
(a) O-R, wherein R i~ a substituted or unsubstituted aliphatic, aromatic, or aralkyl group havin~ from 1 to 10 carbon atoms. Preferably, R i5 an alky]. group. (The re~ulting C-terminal sub~tituted peptide i.5 sometimes hereinafter referred to a~ a C-terminal aster.);
(b) ~H-NH2 (T~..e re~ultinq C-terminal sub~tituted peptide is sometimes referred to a~ a C-terminal h~dra~.ide.!;

SUBSTITUTE SHEET

'' ili214 .
W092/22317 PCT/US92/0~3

-2-(c) NH-OH (The resulting C-terminal substituted peptide is sometimes hereinafter referred to as a C-terminal hydroxylamine.);
(d) N ~

, wherein R' and R" are hydrogen or selected from the cla~s consisting of group (i) and group (ii), wherein;
group (i) i~ a hydroxy-substituted aliphatic, aromatic, or aralkyl group having no more than 10 carbon atoms. Preferably, group ~ a hydroxy-~ubstituted alkyl group. Most preferably, group ~i) i8 CH2CH20H. Group (ii) is an amino-substituted aliphatic or aromatic, aralkyl, or alkylaromatic group.
Preferably the amino-substituted group has no more than 10 carbon atoms. Preferably, group (ii) is an amino-~ubstituted alkyl - group. Most preferably, group (ii) is CH2CH2NH2. The peptides terminated with group (d) are ~ometimes hereinafter referred to a~ substituted C-terminal amide~.
A~ hereinabove stated, the peptide or protein is an ion channel-forming peptide or protein.
An ion channel-forming peptide or protein or ionophore is a peptide or protein which increa~e~ the permeability for ions acro~s a natural or synthetic lipid membrane. B~ Christensen et al. PNAS Vol. 85 Pg~. ~072-76 (July, 1988) describe~ methodology which indicates whether or not a peptide or protein ha~ ion channel-forming properties and i~ therefore an ionophore. As u~ed herein an ion channel-forming peptide or ion channel forming protein i8 a peptide or prokein which haQ ion channel-forming properties as determined by the method of Christensen et al.
An amphiphilic peptide is a peptide which i~cludes both hydrophobic and hydrophilic peptide regions.
Applicant~ have found that, when the C-terminal of ~he biologically active peptides i~ substituted with one of the group~ hereinabove described, such peptides have increased " , SUBSl ITUTE SHEET

---` 2 ~
'WO92~22317 PCT/US92/~ ~3 biological activity as compared with peptides having unsubstituted C-terminals.
The ion channel-forming peptide~ employed in the present invention are generally water soluble to a concentration of at least 20 mg/ml at neutral pH in water. In addition, the structure of such peptide provides for flexibility of the peptide molecule. Such peptides are capable of fo~ming an alpha-helical struct assume an amphiphilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself into a rod-like structure.
In general, such peptides have at least 7 amino acids, and preferably at least 20 amino acids. In most cases, such peptides do not have in excess of 40 amino acid~.
In general, the peptide or protein is administered topically at a concentration of f~om .05% to 10~. When administered systemically, the peptide or protein is employed to provide peptide or protein dosages of from lmg to 500mg per kilogram of host weight.
The compositions may be admini~tered to a host; for example a human or non-human animal, in an amount effective to inhibit growth of a target cell. Thus, -for example, the compositions may be uQed as antimicrobial agents, anti-viral agents, antibiotics, anti-tumor agents, antiparasitic agents, antifungal agents, spermicides, as w@ll as exhibiting other bioactive functions.
The term "antimicrobial" a~ u3ed herein means that the peptide~ of the pre~ent invention inhibit, prevent, or destroy the growth or proliferation of microbes such as ba~teria, ~ungi, or the like.
The term "antibiotic" a~ used herein means that the peptides employed in the present invention produce effectq adver~e to the normal biological functions of the non-host cell, ti~sue, or organism including death or destruction and prevention of the growth or proliferation of the non-host cell, tissue, or organism when contacted with the peptides.

SUBSTITUTE SHEET
, .

WO g2/22317 ~ 1 1 1 2 1 4 PCT/US92/~U~

- The term "spermicidal" as used herein means that the peptides employed in the present in~ention, i~ihi.bit, prevent, or destroy the motility of sperm.
The term "antiviral" as u~ed herein means that the peptides employed in the present invention i~ibit, prevent, or destroy the growth or proliferation o virl~3es, or virally-infected cells.
The term anti-tumor as used herein means that the peptide inhibits the qrowth of or de~troy~ ~umors.
The term "antifungal" a~ u~ed herein means that the peptides of the present invention may be u~ed to inhibit the growth of or de~troy~ fungi.
The term "antipara~itic" as used herein mean~ that the peptides of the present invention may be u~ed to inhibit the growth of or destroy parasite~.
The peptide~ of the present invention have a broad range of potent antibiotic act.ivity against a plurality of microorganisms includlng Gram-po~itive and Gram-negative bacte~ia, fungi, protozoa, and the like, a~ well as parasites. The peptides of the pre~ent invention allow a method for treating or controLling microbial infection cau~ed by organi~m~ which are ~en~itive to the peptides. Such treatment may compri~e administering to a ho~t organism or ti~sue susceptible to or affiliated with a microbial infection an antimicrobial amount of at least one ~f the peptides.
Becau~e of the antibiotic, antimicrobial, and antiviral propertie~ of the peptides, they may also be u~ed as pre~e~atives or sterilants of materials susceptible to microbial or viral contamination.
~ le peptide and/or derivatives or analogue~ thereof may be admini~tered in combination ~rith a ~on-toxic pharmaceutical carrier or vehicle such a~ a filler, non-toxic buffer, or phy~iological ~aline ~olution. Such pharmaceu~ical compositions ~ may be used topically or ~y~temically and may be in any suitable '`;

,~
: :' SUBSTITUTE SHEET

, ~ , -~ 2i.~12 i~l W092/22317 PCT~US92/~K03 form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like. The peptide composition~ may also be u~ed in combination with adjuvants, protein inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in controlling infection caused by harmful microorganisms including protozoa and the like, as well as by parasites and viruses.
The peptide(s) of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or anti-parasitic and/or an antispermicidal amount.
Depending on the u~e, a composition in accordance with the invention will contain an effective anti-microbial amount and/or an effective antispermicidal amount and/or an effective anti-viral amount and/or an effective anti-tumor amount and/or an effective antibiotic amount and/or anti-parasitic amount of one or more of the hereinabove de~cribed peptide~ which have such activity.
The peptide of the present invention may also be employed in promoting or ~ti~ulating healing of a wound in a host.
The term Nwound healing" a~ used herein includes various aspect~ of the would healing process.
These aspects include, but are not limited to, increa~ed contraction of the wound, increa~ed deposition of con~ective' tis~ue, a~ evidencéd by, for example, increa~ed deposition of collagen in the wound, and increa~ed ten~ile stren~th of the wound, i.e., the poptides increa~e wound breaking strength. The peptides of the present invention may also be employed so as to reverse the inhibition of wound healing caused by a depre~ed or comprsmised immune system.
The composition~ of the present invention may also be used in the t`reatment of external burns and to treat and/or prevent skin and burn infections. In particular, the compo~ition~ may be c SUBSTITUTE SHEET

W092~2~t7 2 1 1 1 ~ 1 4 -6- PCT/US92/~

used to treat skin and burn infections caused by organisms such as, but not limited to, P.aeruainosa and S.aureus.
The peptides of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections. In particular, the peptides may be used to treat skin and burn infections cause by organisms such as, but not limited to, P. aeruainosa and S. aureus.
The peptides are also useful in the prevention or treatment of eye infections. Such infections may be caused by bacteria ~uch a~, but not limited to, P. aeruainosa, S. aurous, and N.
aonorrhoeae, by fungi such as but not limited to C. albicans and A. fumiaatu~, by parasite~ such a~ but not limited to A.
ca~tellani, or by viru~es.
The peptide~ may also be effective in killing cysts, spores, - or trophozoites of infection - causing organisms. Such organisms include, but are not limited to Acanthamoeba which forms trophozoite~ or cy~t~, C. albican~, which forms spores, and A.
fumiqatu~, which form~ ~pore~ a~ well. ~ -The peptide~ may al80 be admini Qtered to plants in order to prevent, inhibit, or destroy the growth of microbes, bacteria, fungi, viru~eJ, cy~ts, ~poreq, or para~ite~ in plant~.
~ In accordance with one embodiment, each of ~he amino acid - residue~ of the peptide or protein is a D-amino acid residue or glycine. Although the qcope of this particular embodiment is' not to be limited to any theoretical reasoning, it is believed that the peptido or protein, when consisting entirely of D-amino acid or glycine re~idue~, may have increased resi~tance to proteolytic enzyme~ while retaining their biological activity. Such peptides or proteins thus may be administered orally. Also, in accordance with another embodiment, all of the amino acid re~idues are D-amino acid or glycine re~idues, or ~-amino acid or glycine residues.
In accordance with a preferred embodiment, the peptide is a basic ~positively charged) polypeptide having at least sixteen ,, ~
SUBSTITUTE SHEET

~W092/2U17 PCT/US92/~U~3 amino acids wherein the polypeptide includes at least eight hydrophobic amino acids and at least eight hydrophilic amino acids. Still more particularly, the hydrophobic amino acids are in groups of two adjacent amino acids, and each group of two hydrophobic amino acids is spaced from another group of two hydrophobic amino acids by at least one amino acid other than a hydrophobic amino acid (preferably at lea~t two amino acids) and generally by no greater than four amino acid~, and the amino acids between pair~ of hydrophobic amino acids may or may not be hydrophilic.
The hydrophilic amino acids are generally al~o in groups of two adjacent amino actds in which at least one of the two amino acids i~ a ba~ic hydrophilic amino acid, with such groups o~ two hydrophilic amino acids being spaced from each other by at least one amino acid other than a hydrophilic amino acid (preferably at lea~t two amino acid~) and generally no greater than four amino acids, and the amino acids between pair~ of hydrophilic amino acids may or may not be hydrophobic.
In accordance with a particularly preferred embodiment, the polypeptlde compri~es a chain of at least four group~ of amino acids, with each group con~i~ting of four amino acid~. Two of the four amino ac~ds in each group are hydrophob~c amino acids, and two of the four amino acids in each group are hydrophilic, -with at least one of the hydrophilic amino acids in each group being a basic hydrophilic amino acid and the other being a basic or neutral hydrophilic ~mino acid.
The hydrophobic am~no acids may be selected from the cla~s con~isting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Pro, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and Cyclohexylalanine (Cha). The neutral hydrophilic amino acids may be ~elected from the clasq consisting o A~n, Gln, Ser, and Thr and homoserine - (Hse). The basic hydrophilic amino acid~ may be selected from the cla~ con~i~ting of Lys, Arg, His, Orn, homoarginine (Har), 2, 4 - diaminobu~yric acid (Dbu), and p-aminophenylalanine.

;
,~ ~
:~ SUBSTITUTE SHEET

W~Z/ZZ317 2 1 ~ 1 2 1~ -8- PCT/US92/O~n3 ' Each of the groups of ~our amino acids may be of the sequence ABCD, BCDA, CD~B, or DABC, wherein A and B are each hydrophobic amino acids and may be the same or different, one of C or D is a basic hydrophilic amino acid, and the other of C or D
is a basic or neutral hydrophilic amino acid and may be the same or different. In a preferred embodiment, the polypeptide chain may comprise 5 or 6 groups of thi~ sequence. In each group, each of A, B, C and D may be the fiame in some or all of the groups or may be different in some or all of the groups.
The polypeptide chain preferably ha~ at least 20 amino acids, and no greater than S0 amino acidfi. It i~ to be understood, however, that the polypeptide does not have to con~ist entirely of the group~ de~cribed above. The polypeptide may ha~e amino acids extendin~ from either or both ends of the noted clroup~ forming the polypeptide chain and/or there may be amino acid~ between one or more of the at least four groups and still remain within the scope of the invention.
The groups of amino acids may be repeating groups of amino acids, or the amino acidfi in the variou3 groups may vary pro~ided that in each group of the at least four groups of amino acids there are two hydrophobic and two hydrophilic amino acids as hereinabove noted.
Thus, in a preferred embodimen', the hiologically active polypeptide comprise~ a chain including at leafit four groupfi~of - amino acid~, each containing four amino acids. Two of the four amino Acids in each group are hydrophobic, at least one amino acid is b~ic hydrophilic, and the remainin~ one is basic or neutral hydrophilic, with ~he polypeptide chain preferably having at least 20 amino acid~ but no greater than 50 amino acids.
In one e~bodiment, each of the at least four groups of amino acids which are in the peptide chain i 5 oE the ~equence A-B-C-D, B-C-D-A, C-D-A-B or D-A-B-C wherein A and B ar~ hydrophobic amino acidfi, one of C or D i~ a basic hydrophilic amino acid, and the other of C or D i~ ba~ic or neutral hydrophilic amino acid.

- SUI~STITUTE SHEET

~ 2 ~
;`. ~VO g2/22317 ' PCr/USg2~04603 The resulting polypeptide chain, therefore, may have one of the following seguence~: -(xl)a(A-B-c-D)n(yl)b (X2)a(B-C-D-A)n(y2)b (X3)a(C-D-A-B)n(Y3)b (X4)a(D-A-B-C)n(Y4)b wherein X1 is D; C-D- or B-C-D-, Yl is -A or -A-B or -A-B-C
X2 is A-, D-A- or C-D-A-Y2 is -B, -B-C or B-C-D
X3is B-, A-B-, D-A-B-Y3 is -C, -C-D, -C-D-A
X4is C-, B-C-, A-B-C-Y4 i~ -D, -D-A, -D-A-B
a i~ O or l; b is 0 or 1 and n is at lea~t 4.
It i~ to be understood that the peptide chain may include . amino acid~ between the hereinabove noted group~ of four amino acids provided that the spac~ng between ~uch groups and the : charge on the umino acid~ doe~ not change the characteri~tic~ of : the~pept~de chain which provide amphiphilicity and a positive charge and do not adver~ely affect the folding characteristics of the chain to that which i8 ~ignificantly d~fere~t from one in which the hereinabove noted group of four amino acids are not spaced from each other.
-A~ representative example~ of peptides in accordance with the present invention, there may be mentioned.
I Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Lys-Al~-Phe-Ser-Ly~-Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Lys (SEQ ID NO:1) II Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Lys. (SEQ ID NO:2) III Phe-Ser-Lys-Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Ly~-Ala- (SEQ ID NO:3) Phe-Ser-Ly~Ala-:

SUBSTITUTE SHEET

W092J2~17 2 1 1 1 2 1 4 PCT/US92/~ ~3~

IV Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala- ~SEQ ID NO:4) Phe-Ser-Ly~-Ala-Phe-V Ly~-Ala-Phe-Ser-Ly~-Ala-Phe-Ser-Ly~-Ala-Phe-Ser-1ys-Ala-Phe-Ser (SEQ ID NO:S) The peptide, may have amino acids extending from either end of tho chain. For example, the chains may have a Ser-Lys sequence before the "Ala" end, and/or an Ala-Phe ~equence after the "Ly~" end. Other amino acid sequence~ may also be attached to the "Ala" and/or the n ly~ end.
Similarly, in any polypeptide chain having at least four group~ of amino acid~ of the sequence as described above, the chain may have, for example, a C-D sequence before the fir~t A-B-C-D group. Also other amino acid seguences may be attached to the "A" and/or the "D" end of one of these polypeptide chains.
Al~o there may be amino acids in the chain which space one or more group~ of the hereinabove noted four amino acids from each other.
The peptides with the substituted C-terminals may be ~ynthesized by either solid phase peptide ~ynthe~is or ~olution method~ of peptide ~ynthe~i~. When ~olid pha~e peptide synthe~i6 is employed, the peptlde, with appropriate side chain protection, is synthe~ized by e~tabli~hed methods on a suitable re~in. The protected peptide resin i~ ~uspended in methanol (25 ml/g of re~in) and ~tirred with a large exces~ of an appropriate amino component for ~everal days in order to produce a C-terminal substituted hydrazide, hydroxylamine, or amide having one of the structures herelnabov~ described. When a diamino compound is used, one of the amino group~ i~ suitably protected. The peptide plu8 resin i3 filtered, wa~hed with methanol, and dried. The re d n a~d peptide mixture is subjected to HF treatment and the deprotected peptide amide, hydroxylamine, or hydrazide is extracted with dilute acetic acld and lyophilized.

SUBSTITUTE SHEET

`!W092/22317 2 1 1 1 Z ~ ~ PCT/US92/~603 The C-terminal e~ters can be obtained by transesterification of the peptide with an appropriate alcohol as solvent in the presence of a tertiary base such as triethylamine. The work up and the isolation of the peptide ester is similar to the procedure for isolating the other C-terminal substituted peptides.
When the synthesi~ is carried out by standard solution methods of peptide synthesis, the C-terminal sub6tituted ester peptide may be made by beginning the solution synthesi~ with an appropriate amino acid e~ter. If other modified C-tcrminal peptide~ are de~ired, the protected peptide C-terminal ester may be reacted with hydroxylamine or hydrazine to produce an appropriate peptide C-terminal hydroxylamine or peptide C-terminal hydrazide, respectively.
-If a peptide C-terminal substituted amide i5 desired, the C-terminal e~ter i~ hydrolyzed by standard technique~, and the protected peptide acid is reacted with the desired amino eomponent (suitably protected) by standard coupling procedures.
The prot~cted peptide derivative i~ then deprotected and purified.
It is alsQ pos~ible to produce the peptide~ in un~ubstituted form by genetic engineering techniques. The co~ons encoding the amino acids of the peptide~ are known to tho~e skilled in the art, and thus one may construct DNA encoding any of the pept~ides by accepted technique~, and clone such DNA into an expre~sion vehicle such a~, for example, a plasmid, and transfect such an expre~sion ~ehicle into a cell which will express the peptides.
Upon expres~ion o~ such peptide, the peptide may be sub~tituted at the C-terminal in accordance with the present invention by technique~ æuch a~ tho~e hereinabove de~cri~ed.
In accordance with another preferred embodiment, the peptide may be a maga~.nln peptide.
A magainin peptide i~ either a magainin such as magainin I, II or III or an analogue or deri~ative thereof. The magainin SUBSTlTUtE SHEET

wo g2,223t7 ~ 1 4 PCT/US92/~U~ ~

peptide~ preferably include t:he followin~ basic peptide structure -- Rll-Rll-Rl2-Rl3-Rll-Rl4-Rl2-Rll- ~
R14 R12 R11 R11 Rll R14a ( l5)n 14a 14 wherein R11 is a hydrophobic amino acid, R12 is a basic hydrophilic amino acid; R13 is a hydrophobic, neutral hydrophilic, or baqic hydrophilic amino acid; R14 and R14a are `~
hydrophobic or basic hydrophilic amino acids; R15 is glutamic acid or aspartic acid, or a hydrophobic or a basic hydrophilic amino acid, and n is O or 1. In a preferred embodiment, R13 is a hydrophobic or neutral hydrophilic amino acid, R14a i~ a hydrophobic amino acid, and R15 is qlutamic acid or aspartic acid.
Thus, for example, a ma~ainin peptide may include the . followin~ ~truct~re:
-yl2_xl2_ w~ere Xl~ i 8 the hereinabove described ba~ic peptide ~tructure and Yl~ is (i) R12 (li) R14a ~12 (lii) Rll R14a R12 R14 Rll-Rl4a-p`l2 11~ R12, R14 and R14a are as previously defined A ~ magainin peptide may al~o ha~e the following structur~:

wherein X12 i~ as previ~usly defined alld æl~ is:
- . (1) R16 where R16 is a ba~i_ hydrophili~ nmino acid or aspara~ine or glutamine.
(ii) R16-R17 where R17 i.s a nolltral hydrop~ilic amino acid, a hydrophobic amino acid, or a basic hydrophil~.c amino acid.
Pref~rably, R17 is a no~ltral hydrophilic amino acid.
A magainin peptide may al80 h2.ve the following structure:
(Y12)a-X12 (Z12)b :

~, ~
., ,:
~-~
~ ~ ~ SUBSTITUTE SHEET
, ~ .

`'W092/22317 21~ L~ ; ; PCT/USg2/~Un3 where X~2, Y12 and Z12 are as previously defined and a is O
or l and b is O or 1.
The magainin peptides may also include the following basic peptide structure X13:
-_R14_Rll_R14a_R12_Rll_Rll_R12_R13_ 11 14 12 11 Rll R12-~ wherein Rll'R12'R13' R14~ and R
are amino acid~ aR hereinabove described.
The magainin peptide may also include the following structure Xl3-Z13; wherein X13 is the hereinabove described basic peptide structure and Z13 is _(Rll)n (Rll)n (Rl4a)n (RlS)n (R14a)n ( 14)n ( 16)n ( 17)n rein Rll' Rl4~ R14a~ Rls, Rl6~ and R17 are as hereinabove de~crlbed, and n is O or 1, and each n may be the same or different.
The magainin peptide~ generally include at least fourteen amino acid~ and may include up to forty amino acids. A magainin peptide~preferably ha~ 22 or 23 amino acids. Accordingly, the hereinabove de~cribed ba~ic peptide ~tructures of a magainin peptide may inc}ude additlonal amino acid~ at the amino end or at the carboxyl end, or at both end~.
A~ repre~entative example~ o such magainin peptidefi, there may be~mentioned peptide~ having the following primary sequences -- as given ln the accompanying ~equence listing as well as appropriate analogues and derivative~ theresf:
(a) (SEQ ID NO:6) (Magainin I) (b) (SEQ ID NO:7) ~Magainin II) (c) (SEQ ID NO:8) (Magainin III)~
The following are example~ of peptide derivatives or analogs of the ba~ic structure:
(d) (SEQ ID NO:9) ~- (e) (SEQ ID NO:10) ~ ., SUBSTITUTE SHEET
: ~ ~

,.

W092/22317 21`i~ PCT/US92/OU~3 (f) (SEQ ID NO:ll) Magainin peptide~ are de~cribed in Proc. Natl. Acad Sci.
Vol. 84 pp. 5449-53 (Aug. 87). The term "magainin peptides" as u~ed herein refers to the ba~ic maqainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivatives or analog~.
In accordance with a further embodimen~, the peptide may be a PGLa peptide or an XPE peptide.
A PG~a peptide i~ either PGLa or an analogue or derivative thereof. The PGLa peptide~ preferably include the following basic peptide structure Xl~:
~11 R17 R12 Rll R14 R14 11 Rll R14 R12 Rll Rll R12 Rll Rll Rll R12 where Rll, R12, R14, and R17 are as previously defined.
The PG~a peptldes gen~rally include at lea~t seventeen amino acids and may include a~ many as forty amino acids. Accordingly, the hereinabove deJcribed ba~ic peptide ~tructure for a PG~a peptide may include additional amino ac~ds at the amino end or at the carboxyl end or at both the amino and carboxyl end.
Thus, for ex~ple, a PG~a peptide may have the following ~tructure:

where X14 is a~ previously defined and ,Y14 i (i) Rll;
( ii ) R14-Rll wher~ Rll and R14 are a~ previously defined.
For example, a PGLa peptide may al~o have the following structure:

where X14 is as previou~ly defined; and Z14 i 5:
(i) R11; or ( ii ) Ril-R

S~.IBSTITUTE SHEET

211121g ~WOg2/2~17 PCT/US92/04603 where Rll is as previously defined.
A PGLa peptide may also have the following structure:
(Y14)a 14 14 b where X14; Y14 and Z14 are as previously defined, a is 0 or 1 and b is 0 or 1.
An XPF peptide is either XPF or an analogue or derivative thereof. The XPF peptides preferably include the following basic peptide structure X16:
Rll R17 R12 Rll R14 R18 17 Rll Rl~ R12-Rll-Rll-R12-R11 Rll Rl1 R12~(R15)n~R11~~, wherein R11, R12, Rl~, R15 and R17 are as previously defined and R18 is glutamine or asparagine or a basic hydrophilic, or , hydrophobic amino acid and, n is O or 1.
The XPF peptideR generally include at least nineteen amino acid~ and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.
~ - Thus, for example, an XPF peptide may include the following structure: .
-yl6_xl6_ where X16 i~ as previously defined and Y16 is (i) Rll ~r ( ii ) R14 Rll where Rll and R14 are as previously defined.
An XPE peptide may include the following structure:

where X16 is a~ previously defined and Zl~ is (i) R11; or (ii) R11 R18; or (iii) R11-R18-Proline; or ( iv) R,ll-R18-Prline R12 - SUBSTITUTE SHEET

211121~
WOg2/~17 -i6- PCT/US92/~U~3 An XPF peptide may also ha~e the followin~ structure:
(Y16)a 16( 16)b where X16, Y16 and Z16 are as previously defined: a is 0 or 1 and b is 0 or 1.
Preferred are XPF or PGLa peptides, which are characterized by the following primary amino acid sequence~ as given in the accompanying ~equence li~ting:
PGLa : (SEQ ID N0:12) XPF : (SEQ ID N0:13) A re~iew of XPF and PGLa can be found in Hoffman et al, EMB0 J. 2:711-714, 1983; Andreu et al, J. Biochem. 149:531-535, 1985;
Gibson et al J. Biol. Chem. 261:5341-5349, 1986; and Giovannini et al, Biochem J. 243:113-120, 1987.
In accordance with yet another embodiment, the peptide may be a CPF peptide or appropriate analogue or derviative thereof.
CPF peptide~ as well a~ analogue~ and derivatives thereof are herein ~ometime~ referred to collectively a~ CPF peptides.
The CPF peptide may be oDe which include~ ~he following basic peptide ~tructure X20:
-~ -R -R22-R22-R2l-R2l-R23 -R21-R21 R23 R21 R21 24 25 Zl - wherein R21 i~ a hydrophobic amino acid;
R22 i~ a hydrophobic amino acid or a ba~ic hydrophilic amino acid;
R23 i~ a ba~ic hydrophilic amino acid;
R24 i~ a hydrophobic or neutral hydrophi~ic amino acid; and R25 i~ a basic or neutral hydrophilic amino acid.
The hereinabove ba~ic structure is hereinafter symbolically indicated a~ X20.
The hydrophobic amino acids are Ala, Cy8, Phe, Gly, Ile, Leu, Met, Val, Trp, Tyr, norleucine (Nle), norvAline (Nval), and cyclohexylalanine (Cha).

, ~ , , ~ .
, : , .
, - , , ? SVBSTITUTE SHEET
.
,, ~WOg2/2~17 ~ PCT/US92/~03 The neutral hydrophilic amino acid8 are Asn, Gln, Ser, and Thr.
The basic hydrophilic amino acids are Lys, Arg, His, Orn, homoarginine (Har~, 2, 4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
The CPF peptide may include only the hereinabove noted amino acid~ or may include additional amino acids at the amino and/or carboxyl end or both the amino and carboxyl end. In general, the peptide doe~ not include more than 40 amino acids.
The CPF peptide~ including the above basic structure preferably have from 1 to 4 addltional amino acids at the amino ond.
Accordingly, such preferred peptides may be repre~ented by the structural formula:
Y20 X20 ~.
wherein X20 i~ the hereinabove de~cribed ba~ic peptide structure and Y20 is R25-, or ( ii ) R22 R2s (i~i) R21-R22-R25; or (iv) R22 R21 R22~R25; preferably ., Glycine - El21-R22 R25-wherein R21, R22 and R25 are as previously defined.
The`carboxyl end of the basic peptide structure may als~
have additional amino acid~ which may range from 1 to 13 additional amino acids.
$n a preerred embodiment, the basic structure may have from 1 to 7 additional amino acids at the carboxyl end, which may be represented a~ follows:
-X20 ~ Z20 wherein X is the hereinabove defined basic peptide structure snd Z20 is (i) ~21-~ or ( i i ) R2 1 R2 1 ,', ' SUBSTITUTE SHEET

WO g2/22317 Pcr/uss2/o4603 ~.

(iii) R21-R21-R24; or ( iv) R21-R21-R24 R24;
(v) R21 R21-R24-R24-R26; or (vi) R21 R2l-R24-R24-R26-Gln; or (vii) ~21 R21 R24 R24 R26~Gln~Gln, wherein R21 and R24 are as previously defined, and R26 is proline or a hydrophobic amino acid.
Preferred peptides may be represented by the following structural formula (Y20)a X20 (Z20)b wherein X20, Y20 and Z20 are as previously defined and a is 0 or 1 and b is 0 or 1;.~
Representative examples of CPF peptides which may be '- employed, ~ome cf which have been described in the literature, include the following ~equences as given in the accompanying ~eguence listing:
(SEQ ID N0:14) ---(SEQ ID N0:15) (SEQ ID N0:16) (SEQ ID N0:17) (SEQ ID N0:18) (SEQ ID N0:19) (SEQ ID N0:20) (SEQ ID N0:21) (SEQ ID N0:22) (SEQ ID N0:23) (SEQ ID N0:243 (SEQ ID N0:25) (SEQ ID N0:26) The above is expressed a~ single letter code for amino acids.

,' SUBSTITUTE SHEET

-- . .
~WO92/22317 2 1 ~ PCT/USg2/~U~3 --19-- ., A review of the C~F peptides can be found in Richter, K-, Egger, ~.
R., and Kreil (1986) J. Biol. Chem 261, 3676-3680; Wakabayashi, T., Kato, ~., and Tachibaba, S. (1985) Nucleic Acids Re~earch 13, 1817-1828; Gibson, B.W., Poulter, L., Williams, D.H., and Maggio, :
J.E. (1986) J. Biol. Chem 261, 5341-5349. :
In accordance with yet another embodiment, the peptide may :
include one of the following basic ~tructures X31 through X37 wherein:
X31 i~ ~[R3l-R32-R32-R33-R3l-R32-R32l~n;
X32 is IR32 R32 R33 R31 R32 R32 R311 n;
X33 i~ IR32 R33 R31 R32 R32 R31 R32] n;
X34 i~ ~R33 R3l-R32-R32-R3l-R32-R32l~n;
X35 i8 ~R3l-R32-R32-R3l-R32-R32-R33l-n;
X36 i~ IR32 R32 R31 R32 R32 33 31] n;
~, X iS -~R32-R3l-R32-R32-R33-R3l-R32l-n;
wherein R31 is a ba~ic hydrophilic amino acid, R32 i~ a hydrophobic amino acid, R33 is a neutral hydrophilic or hy~rophobic amino acid, and n i~ from 2 to S.
: The ba~ic hydrophilic amino acids may be selected from the class con~i~ting of Ly~, Arg, His, Orn, homoarginine (Har), 2, 4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
The hydrophobic amino acid~ may be selected from the class con~isting of Ala, Cy~, Phe, Gly, Ile~ Leu, Met, Val, Trp and Tyr,norleucine (Nle?, nor~aline (Nva), and cyclohexylalaniné
(Cha) The neutral hydrophi~ic amino acid~ may be selected from the cla~ con~isting of A~n, Gln, Ser and Thr.
In accordance with one embodiment, when the peptide includes the structure X31, the peptide may include the following ~tructure:~
Y31-X31, wherein X31 i~ a~ hereinabove described, and Y
is:
(i) R32;
;' (ii) R32-R32;

SUBSTITUTE SHEET

WO92/22317 ~ 2 1 ~ PCT/US92/~ ~3 (iii) R31-R32 R32;
(iV) R33-R31-R32 R32;
(v) R32-R33-R31 R32 R32;
(vi) R32 R32 R33 R3l-R32-R32~ wherein R31, R32, and R33 are as hereinabove described In accordance with another embodiment, when the peptide includes the structure X31, the peptide may include the following structure:
X31-Z31, wherein X31 is as hereinabove described, and Z31 i~:
(i ) R31; :
(ii) R31 R32;
(iii) R31-R32 R32;
(iv) R31-R32 R32 33 (v) R31-R32-R32-R33-R31; or (v~) R31 R32 R32 R33 R31 R32-In accordance with yet another embodiment, the peptide mayinclude the followinq structure:
(Y3l)a-x3l-(z3l)s~ wherein Y31 and Z31 are as previou~ly defined, a i8 0 or 1, and b i~ O or 1.
When the peptide include~ the structure X32, the peptide may include the following structure: ~
Y32 - X32~ wherein X32 is as hereinabove described, and Y32 is:
(i) R31;
(ii) R32-R31;
(iii) R32-R32 R31;
~ iv) R31~R32 ~32 ~31;
(v) R33 ~31 R32 R32 31;
(vi) R32-R33-R31 R32 ~32 R31 In another embodiment, when the peptide includes the structure X32, the peptide may include the following ~tructure:
X32 ~ Z32~ wherein X32 i as hereinabove described, and Z32 is:

SUBSTITUTE SHEET

t ,r W092/2~17 PCT/US92/~U~3 (i) R32;
(ii) R32-R3?;
(iii) R32-R32 R33;
(iv) R32-R32 R33 R31;
(~) R32 R32 R33 31 32;
(Vi ) R32-R32-R33-R31-R32-R32 :
In accordance with yet another embodiment, the peptide may include the ollowing ~tructure:
(Y32)a X32 (Z32)b' wherein Y32 and Z32 are as previously defined, a i8 0 or 1, and b i8 0 or 1.
I~ accordance with another embodiment, when the peptide include~ the ~tructure X33, the peptide may include the following ~tructure:
Y33 - X33 wherein X33 i~ a~ hereinabove de~cribed, and Y33 , (i) R32;
(ii) R31 R32;
( iii ) R32-R31 R32;
(iv) ~ 2-~ 2-R31 R32;
) 31 R32 R32-R31-R32; or ( ) 33 R31 R32 R32 R31 R32~ wherein R31, R32, and R33 are ~-~ a~ hereinabove de~cribed.
In accordance with another embodiment, when the peptide include~ the ~tructure X33, the peptide may include the foll~wing structure:
X33 - Z33 wherein X33 i~ aR hereinabove de~cribed, and Z33 i E :
:~ (i) R32;
(ii) R32 R33;
(iii) R32-R33 R31;; f, (iv) R32-R33-R31 R32;
v) R32-R33-R3l-R32-R32; or (Vi ) R32-R33-R31 R32 R32 R3 , ~ .
: ,~
,.. , ~ , , ,. - .
,. ..,~

SUBSTITUTE SHEET

W092/2__.. ? ~ PCT/US92/~03 In accordance with yet another embodiment, the peptide may include the following structure:
(Y33)a X33 (Z33)b' wherein Y~3 and Z33 are as previously defined, a is 0 or 1, and b is 0 or 1.
In accordance with yet another embodiment, when the peptide includes the structure X34, the peptide may include the following structure:
Y34 - X34, wherein X34 i~ as hereinabove de~cribed, and Y34 i s :
(i) R32;
(ii) R32 R32;
) R3l-R32 R32;
(iv) R3 Y2-R3l-R32 R32;
(v) R32-R32-R31-R32-R32; or ( i) R31 R32 R32 R31 R32-R32~ wherein R31, R32 and R33 are as hereinabove de~cribed.
In accordance with another embodiment, when the peptide includes the ~tructure X34, the peptide may include the following structure: ;
X34-Z34, wherein X34 i8 as hereinabove de~cribed, and Z34 : (i) R33;
(ii) R33 R31;
~iii) R33-R31 R32;
(iv) R33-R31-R32 R32;
( ) ~33 R31 ~32-R32-R31; or (vi~ R33-R3l-R32-R32 R31 R32 In accordance w~th yet anoth¢x embodiment, the peptide may include the following ~tructure:
(Y34)a X34 (Z34)b' wherein X34 and Z34 are as previously defined, a i8 .0 or 1, and b is 0 or 1.
In accordance with a further embodiment, whe~ the peptide includes the struGtur~ X35, the peptide may include the followin~
structure:

,~: ' ' ,. , SUBSTITUTE SHEET
';: ' ' ~ W09U22317 211 121~ PCT/US92/0~3 -2~-Y35-X35, wherein X35 is as hereinabove described, and Y35 ~:
is:
(i) R33;
(ii) R32 R33;
(iii) R32-R32-R33;
(iv) R3l-R32 R32 33 (v) R32-R3l-R32 R32 33 (vi) R32 R32 R3l R32 R32~R33, wherein R3l, R32, and R33 are a~ hereinabove de~cribed.
In accordance with another embodiment, when the peptide include~ the ~tructure X35, the peptide may include the following ~tructure:
X35 - Z35 wherein X35 is as hereinabove de~cribed, and Z35 i8:
(i) R31;
(~) R3I-R32;
) R3l-R32 R32;
( iv ) R3 1-R32-R32 R3 1;
(v) R3l R32-R32-R3l-R32; or (Vi ) R31-R32-R32-R31 R32 R32 :
In accordance wlth yet another embodiment, the peptide may include the followin~ Jtructure: ' (Y3S)a X35 (Z35)b~ wherein X35 and Z35 are as previously ~ defined, a i8 0 or l, and b i~ O or l.
: In accordance with a further embodiment, when the peptide includes the structure X36, the peptide may include the following - structure:
Y36 ~ X36 wherein X36 i8 a~ hereinabove described, and Y36 is:
(i) R31; , (ii) R33-R31;
(iii) R32~R33 R3l;
(iv) ~32~R32~R33 R3l;
(v) R3l ~32 R32 R33 R3l;

,, ~

, -SUBSTITUTE SHEET

wo Y~ i 1 1 2 1 4 : PCT/US92/~U~3 ~~l ( ) R32 R31 R32 R32 R33-R31, wherein R31~ ~32' and R33 are as hereinabove descr$bed.
In accordance with another embodiment, when the peptide includes the structure X36, the peptide may include the following structure:
X36-Z36, wherein X36 is as hereinabove described, and Z36 is:
(i) R32;
(ii) R32-R32;
(~ii) R32-R32 R31;
6~V) R32-R32 R31 R32;
(~) R32 R32 R31 R32 R32;
(vt) R32-R32-R31 R32 R32 33 In accordance with yet another embodiment, the peptide may include the following structure:
~ Y36)a X36 (Z36)b~ wherein Y36 and Z36 are a~ previously deined, a i8 0 or 1, and b i~ O or 1~
In accordance with one embodiment, when the peptide includes ~- the ~tructure X37, the peptide may includes the structure Y37-X37, wherein X37 is as hereinabove described, and Y37 is:
(i) R32;
( i~ ) R31-R32;
(iii) R33-R31 R32;
(iv) R32~R33~R31 ~32;
~v) R32-R32-R33-R31 R32;
(vi) R31 ~32 R32 R33~R31~R32~ wherein R31, R32, and R33 are as hereinabove de~cribed.
In accordance wtth a further embodiment, when the peptide includes the structure X37, the peptide may include the following structure:
X37 - Z37 wherein X37 is as hereinabove described, and Z37 is:
` (i) R32;
(ii) a32-~31 , ,:
~,,, S~JBSTITUTE SHEET

, WO92/22317 PCT/US92/~3 21 Ll~1~2s (iii) R32-R31 R32;
(iv) R32-R31-R32 R32;
(v) R32-R31-R32 R32 ~33;
(Vi ) R32-R31-R32-R32-R33-R3~
In accordance with yet another embodiment, the peptide may include the following structure:
(Y37)a~ X37 (Z37)b~ wherein Y37 and Z3~ are as previously defined, a is 0 or 1, and b i~ 0 or 1.
In a preferred embodiment, n i~ 3, and mo~t preferably the peptide ha~ one of the following ~tructures:
(Ly~ Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO:27).
(Ly~ Ile Ala Ly~ Ile Ala Gly)3 (SEQ ID NO:28).
(Ly~ Ile Ala Gly Ly~ Ile Gly)3 (SEQ ID NO:29).
(Lys Leu Ala Gly Ly~ Leu Ala)3 (SEQ ID NO:30).
~ (Lys Phe Ala Gly Ly~ Phe Ala)3 (SEQ ID NO:31).
(Ly~ Ala Leu Ser Lys Ala Leu)3 (SEQ ID NO:32) (Lys Leu Leu Lys Ala Leu Gly)3 (SEQ ID NO:33) (Lys Ala Ile Gly Ly~ Ala Ile)3 (SEQ ID NO:34) (Gly Ile Ala Ly~ Ile Ala Ly~)3 (SEQ ID NO:3S) (Ly~ Ile Ala Lys Ilc Phe Gly)3 (SEQ ID NO:36) (Gly Ile Ala Arg Ile A}a Ly~)3 (SEQ ID NO:37) (Lys Phe Ala Arg Ile Ala Gly)3 (SEQ ID NO:38) (G}y Phe Ala Lys Ile Ala Lys)3 (SEQ ID NO:39) (Ly~ Ile Al~ Gly Orn Ile Ala)3 (SEQ ID NO:40) (Ly~ Ile Ala Arg Ile Ala Gly)3 (SEQ ID NO:41~
(Orn Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO:42) (Gly Ilo Ala Arg Ile Phe Ly~)3 (SEQ ID NO:43) (Ly~ Nle Ala Gly Ly~ Nle Ala)3 (SEQ ID NO:44) (Ly~ Nle Ala Gly Lys Ile Ala)3 (SEQ ID NO:45) (Ly~ Ile Ala Gly Ly~ Nle Ala)3 (SEQ ID NO:46) (Ly~ Nva Ala Gly Ly~ Nva Ala)3 (SEQ ID NO:47) (Lys Nva Ala Gly Ly~ Ile Ala)3 (SEQ ID NO:48) (Lys Leu Lcu Ser Lys Leu Gly)3 (SEQ ID NO:49) (Lys Leu Leu Ser Ly- Phe Gly)3 (SEQ ID NO:50) SUBSTITUTE SHEET

-wog2~22317 . 2111214 -26- PCT/US92/~3~ ;

(Lys Ile Ala Gly Lys Nva Ala)3 (SEQ ID NO:51) (His Ile Ala Gly His Ile Ala)3 (SEQ ID NO:52) (Ala Gly Lys Ile Ala Lys Ile)3 (SEQ ID NO:53) (Ile Ala LYF?5 Ile Ala Gly Lys)3 (SEQ ID NO:54) (Lys Ile Ala Gly Arg Ile Ala)3 (SEQ ID NO:55) (Arg Ile Ala Gly Arg Ile Ala)3 (SEQ ID NO:56) (Lys Val Ala Gly Lys Ile Ala)3 (SEQ ID NO:57) (Lys Ile Ala Gly Ly~ Val Ala)3 (SEQ ID NO:58) (Ala Lys Ile Ala Gly Lys Ile)3 (SEQ ID NO:59) (Orn Ile Ala Gly Orn Ile Ala)3 (SEQ ID NO:60) (Lys Phe Ala Gly Lys Ile Ala)3 (SEQ ID NO:61) (Lys Ile Ala Gly Ly~ Phe Ala)3 (SEQ ID NO:62) ~`
(Lys Cha Ala Gly Ly~ Ile Ala)3 (SEQ ID NO:63) (Lys Nle Ala Lys Ile Ala Gly)3 (SEQ ID NO:64) . (Arg Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO:65) (Har Ile Ala Gly Har Ile Ala)3 (SEQ ID NO:66) (Xaa Ile Ala Gly LYJ Ile Ala)3 (SEQ ID NO:67) - : (Lys Ile Ala Gly Xaa Ile Ala)3 (SEQ ID NO:68) (Lys Ile Ala (Ly~ Ile Ala Gly Lys Ile Ala)3 tSEQ ID NO:69) In (S~Q ID NO:67) and (SEQ ~D NO:68), Xaa is p-aminoph-nylalanine.
~ In accordance with another embodiment, the b'iologically -~ ~ active amphiphilic peptide which include~ the following ba~ic structure X40 R -R -R -R -R34_R32_R32_R31-R32-R32-R32-R34-R32-R32, wherein R31, R32, and R33 are as hereinabove de~cribed, and R34 is a bad c hydrophilic or hydrophobic amino acid.
In accordance with one embodiment, the peptide may include the following tructure:
Y40-X40, wherein X40 is as hereinabove described, and Y40 iq:
(i) R32;
(ii) R32 R32;
(iii) R34 R32 R32;

SUBSTITUTE SHEET

,,,.,~ ~
~L~--~'.~,L,5' ,.'~'LI.t.'',;-,.'.^.~5 ;.,',';,.. 5.~5_.~tï '~ Y.~r~ ,Y, ~ '~,L~'-~ ~i,'~` .~:`'` .: ~'`':

: ` WOg2J22317 - PCT/US92/~ ~3 21~ 4 -27-(iv) R33-R34-~32 R32;
(v) 32 R33 R34_R32_R32;
(v) R32 R32 R33 R34-R32-R32' or ( ) R31 R32 R32 R33-R34-R32-R32~wherein R31~ R32~ ~33 and R34 are as hereinabove de~cribed.
In accordance with another embodiment, the peptide may include the following structure:
X40-Z40, wherein X40 i~ as hereinabove de~cribed and Z40 is:
(i) R3~
(ii) R31 R32;
(iii) R31-R32 R32;
(lv) R31-R32 R32 R33;
(v) R31-R32-R32 R33 R34;
(vi) R31-R32-R32-R33-R34-R32; or ( i) R31 R32 R32 R33~R34~R32~R32, wherein R31, R32, R33, and R34 are a~ hereinabove described.
In accordance with yet another embodiment the peptide may include the following structure:
(Y40)a X40-(Z40)b~ wherein Y40 and Z40 are a~ previou81y defined, a i8 0 or 1, and b i8 0 or 1. In a preferred embodiment, the peptide has the following ~tructural formula as : given in the accompanying seguence listing:
(SEQ ID N0:70) In another preferred embodiment, the peptide has the following structural formula a~ given in the accompanying ~equence li~ting:
(SEQ ID N0:71) In accordance wi~h a further embodiment, the peptide ha~ one of the following structural formulae a~ given in the accompanying ~equence li~tin~
(SEQ ID N0:72) (SEQ ID N0:73) (SEQ ID N0 74) (SEQ -ID N0:75) ;'":," ' SUBSTITUTE SllEET
.

wog~ 2 1 1 1 2 1 4 28- PCT/USg2/04603 ~

(SEQ ID N0:76) (SEQ ID N0:77) (SEQ ID N0:78) (SEQ ID N0:79) (SEQ ID N0:80) (SEQ ID N0:81) (SEQ ID N0:82) (SEQ ID NO:83) (SEQ ID N0:84) (SEQ ID N0:8S) ~;
(SEQ ID N0:86) (SEQ ID NO:B7) In accordance with another embodiment, the peptide may include the following ~tructurai formula:
-(Ly~ Ile Ala Ly~ Lys Ile Ala)-n, wherein n is from 2 to 5.
Preferably, n ~8 3, and the peptide ha~ the following structural formula:
(Ly~ Ile Ala Lys Lys Ile Ala)3 (SEQ ID N0:8~) In accord~nce with another embodiment, the peptide may ~nclude th~ following ~tructural formula:
_(~ys Phe Ala Lys Ly~ Phe Ala)~n wherein n iq from 2 to 5.
: Preferably, n i~ 3, and the peptide has the following ~tructurai formula:
(Ly~ Phe Ala Lyq Lys Phe Ala)3 (SEQ ID N0:89~
In accordance with another embodiment, the peptide may include the following ~tructural formula:
-(Ly~ Phe Ala Lys Lys Ile Ala)~n wherein n is $rom 2 to 5. Preferably n i8 ~, and the peptide has the following ~tructural formula:
tLys Phe Ala Lys Lys Ile Ala)3 (SEQ ID N0;90).

` ~ SUBSTITUTE SHEET

W092/22317 2 i 1 ~ 2 ~ 29- PCT/US92/~U~3 ,~

In accordance with another embodiment, the peptide is selected from the group consisting of the following ~tructura formulae as given in the accompanying seguence listing:
(SEQ ID NO:9l) (SEQ ID NO:92) (SEQ ID NO:93) (SEQ ID NO:94) In accorda~ce with another ambodiment, the peptide includes the following basic structure X50:
R4l R42 R42 R4l R42 R42 R4l R4l 42 41 41 R41 i8 a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
In one embodiment, the peptide includes the basic structure YSo -X50 wherein X50 i8 as hereinabove de~cribed and YSo is:
,, (i) R41;
(ii) R42 R4l; or (iii) R42-R42-R4l, wherein R4l and R42 are as hereinabo~e de~cribed.
In one embodimënt, R41 i8 leucine. In another embodiment, R42 i~ ly~ine. Representative examples of peptides in accordance with this aspect of the pre~ent invention include those having the following ~tructures:
(SEQ ID NO:95) (SEQ ID NO:96) (SEQ ID NO:97) (SEQ ID NO:98) In accordance with another èmbodiment, the peptide includes the following basic structure XS2:
R42 R4l R42 R42 R4l R4l R42 42 41 42 42 41 i~ a hydrophopbic amino acid and R42 is a ba~ic hydrophilic or neutral hydrophilic amino acid.
In one embodiment R41 is leucine. In another embodiment, R42 is ly~ine.

~' . ~

- SUBSTITUTE SHEET

W092/2~17 2 1 1 1 2 1~ -30- PCT/US92/04603~

In one em~odiment, the peptide includes the basic structure Y5~ -X52, wherein X52 is as hereinabove described, and YS2 is:
(i) R42;
(i~) R41-R4~;
(iii) R4l R4l 42;
(i~) R42-R4l-R4l-R42;
(v) R42 ~42 R4l R4l-R42-In one emodiment, the peptide may have the following structure;
Ly~ Ly~ Leu Leu Ly3 Lys Leu Lys Lys Leu S lt) Leu Ly~ Ly~ Leu Arg Arg (SEQ ID NO:99) In another em~odiment, the peptide includes the ba~ic ~tructure X!;2-ZS2, wherein X~;2 is as hereinabove described, and Z52 i~:
(i) R41;
( il ) R41 R41;
(iii) ~41 R4l R42;
(iv) R4l R4l R42 R4~;
(~) R4l R4l R42 R42 ~l;
I~ one embodiment, the peptide may have the following structure: , Ly~ Leu Lys Lys Leu Leu Ly~ Ly~ Leu Lys Lys Leu L~u Lys Lys Leu 5 lO 15 (SEQ ID NO:~00)-In ano~her embodiment, the peptide may include the ~tructure:
(Y ) ~ XS2 ~ (Z52)b~ wherein XS2, Y52, S2hereinabove de~cribed, and a is O or l, and b i~ O or l.
In accordance with another embodiment, the peptide ~ncludes the following basic ~tructure XS4:

R4l-R42-R42-R4l'R4l R42 ~42 ~41 R42 42 41 41 42 42 43 SUBSTITUTE SHEET

WO92/22317 '~ 1 1 1Z 1~ _31- PCT/USg2/~K~3 wherein R41 and R42 are a~ hereinabove described, and R43 is a netural hydrophilic amino acid.
In one embodiment, the peptide may ha~e the following ~tructure:
(SEQ ID N0:101) In another embodiment, the peptide may have the following structure:
(SEQ ~D N0:102) In accordance with yet another embodiment, the peptide include~ the following ba~ic ~tructure X56:
41 R42 R41 R41 R42 R42~R41~R41~R42~R42~R44, wherein R41 and R42 are a~ hereinabove d~cribed, and R44 i~ a neutral hydrophilic amino acid or proline.
In one embodiment, the peptide may include the following ~tructure YS6-X56, wherein X56 is the ba~ic peptide structure hereinabove de~cribed, and YS6 i~:
(i) R41 .:
~11) R41 a4l;
(iil) -R42-R41 R41;
(iv) R4l R42 R41 R41;
~ (v) R41 R41 R42 R41 41;
:~ (vi) R42 R41 R4l-R42-R4l-R4l; or (vii) -R42-R42-R4l-R4l-R4l-R42-R4l-R4l~
wherein R41 and R42 are aQ hereinabove described.
In one embodiment, the peptide may include the structure:
XS6-Z56, wherein X56 i~ a~ hereinabove de~cribet, and Z56 i~:
(i) R42;
(ii) -R42-R42;
(iii) R42 R42 ~41;
.
(iv) -~42-R42 R41- 41 (v) R42 R42 R41~R41 42;
(vi) -R42-R42-R41 R41-R42-R42; or (vii) R42 R42 R41_R41 R42 42 41 ,, , i ~ .
", . .

~, ~-;.
: ~ - : SUBSTITUTE SHEET
,.,, ~

wo g2/223l7 2 1 1 ~ 2 1~ PCT/US92/~U~3 In a preferred embodiment, the peptide may have one of the following structures:
(SEQ ID N0:103); or (SEQ ID N0:104).
In another emodiment, the pèptide may have the structure (Y56)a-X56-(Z56)b, wherein X56, Y56, and ZS6 are as hereinabove de~cribed, a i~ 0 or 1, and b i~ 0 or 1.
In accordance with another embodiment, the peptide includes the following basic ~tructure X58:

wherein R41, R42 and R43 are a~ hereinabove de~cribed.
In accordance with another embodiment, the pcptide may include the ~tructure Y58-XS8, wherein XS8 is as hereinabove de~cribed, and Y58 i~:
(i) -R41;
( ii ) -R42-R41;
(iii) R42 R42 R41;

(iv) R41 R42 R42-R41; ..
(v) -R41 R41 R42-R42 R41;
(vl) -R42-R41-R41 R42-R42-R41; or (Yii ) R42 R42 R41-R41-R42-R4~-R41~ wherein R41 ~nd R42 are as hereinabove d~scribed.
In another e~bodiment, the peptide includes the ~tructure X58-ZS8, wherein X58 i~ a~ hereinabove de~cribed, and ZSB is:~
(i) -R41;
(ii) -R41-R45;
(iii) R41 R45 R45;
: (iv) -R41-~45-R45-R43;
(v) -R41-R45-R45_R43 R41;
(vi) -R41-R45-R45-~43 ~41 R43;
(vii) -R41 R45 R45_R43 R41 43 43 (viii) -R41-R45-R45 R43-R41-~43-R43'-R45; or ; (ix) R41 R45 R45-R43-R4i-R43-R43~-R4S-R43~ whereln R
and R43 ~re as hereinabove de~cribed, and R45 is prollne.
: In one embodiment, the peptide has the following structure:

SUBSTITUTE SHEET

`^ ` wo g2/223l~ 2 ~ 1 1 2 1~ PCT/US92/~4~3 In one embodiment, the peptide may have the structure (Y58)a-xs8-(zs8)b~ wherein X58, Y5~, and Z58 are a~ hereinabove described, a i8 0 or 1, and b is 0 or 1.
In accordance with another embodiment, the peptide includes the following ba~ic structure X60;
R41-R4l-R43-R42-R41 R41 R41 R41 R41 R4l R42 R41 41 42 42 41 R41-R42-R42-R42-R41~ wher~in R41, R42, and R43 described. In one e~bodiment, the peptide may have the following ~tructure:
(SEQ ID N0:106). -~
In another e~bodiment, the peptide may include the ~tructure X60-Z60, wherein X60 i~ a~ hereinabove de~cribed, and Z60 i~:
(1) R42; ,::
(ii) -R42-R42;
,, (il~) R42 R42 R41; , (iv) R42 R42 R41-R41; :
(v) R42 R42-R41_R41-R42;
(v~) -R42-R42-R41_R41-R42-R42; or (vli) R42 R42 R41_R41 R42 42 41 In accordance with yet another embodiment, the peptide ha~ a ~tructure select~d from the group con~i~ting of (a) R -R42-~42-R4l-R42-R42-R4l;
(b) R41-R41-R42 R42 R41 R42 R42 41;
(c) R42~R41~R41~R42~R42 R41 R42 R42 R41;
(d) R -R ~~ -R41_R42_R42-R41-R42-~42-R41; and (e) R4l-R42-R42-R4l-R4l-R42-R42-R4l-R42-~42-R4l~ wherein R41 and R~2 are a~ herein~bove de~cribed.
In one embodiment, the peptide ha~ the structure (a), and a repre~entative example of ~uch a ~tructure is (5EQ ID N0:107), which i~ given in the accompanying ~equence listing.
In ano~her embodiment, the peptide has the ~tructure (b), and a repre~entative e~ample of ~uch a ~tructure is (SEQ ID

N0:108), which 1~ given in the accompany1ng sequence l1~ting.

, ~

SUBSTITUTE SHEET

~ -21~2 14 -:
WOg2/223l7 _34_ PCT/USg2/~ ~3;

In another em~odiment, the peptide has the structure (c), and a representative example of such a structure i9 (SEQ ID
N0:109) as given the accompanying sequence listing.
In yet another embodiment, the peptide has the structure (d), and a representative example of s~ch a structure is (SEQ ID
N0:110) as given in the accompanying ~equence listing.
In a further embodiment, the peptide has the structure (e), and repreJentative examples of such a structure are (SEQ rD
N0:111) and (SEQ ID N0:112) as given in the accompanying sequence listing.
In accordance with another embodiment, the peptide has the following structural formula:
(SEQ ID N0:113).
In accordance with yet another embodiment, the peptide may be a cecropin or sarcotoxin.
The term ~ecropin~ includes the basic ~tructure as well as analogue~ and derivative~ thereof. The cecropins and analogue~
and derivativ~s th~r~of are de~cribed in Ann. Rev. Microbiol.
1987, Vol. 41, pages 103-26, in particular page 108, and in Christen~en, et al., PNAS Vol. 85, pgs. 5072-76, which are hereby incorporated by reference.
The term ~arcoto~ins includes the basic materials as well as analogues and derivativos th~reof. The ~arcotoxins and analogues and derivatives thor~o are described in Molecular Entomolo~y~
pag2s 369-78, in partlcular page 375, Alan R. Liss, Inc. (1987), which i8 ~ereby incorporated by refèrence.
Ion channel-forming proteins or peptides which may be employed include defensin , also known as human neutrophil antimicrobial peptides (HNP), major ba~ic protein (MBP) of eosinophils, bactericidal perme~bility-increasing protein (8PI), and a pore-forming cytotoxin called variously perforin, SUBSTITUTE SHEET

WOg2/2~17 2 11 ~21 ~ -35- PCT/US92/~U~3 cytolysin, or pore-forming protein- Defensins are described in Selsted, et al., J. Clin. Inve~t., Vol. 76, pgs. 1436-1439 (1985). MBP protein~ are de~cribed in Wasmoen, et al., J. Biol.
Chem., Vol. 263, pg~ 125Sg-12563. (1988). BPI proteins are described in Ooi, et al, J. Biol. Chem., Vol. 262, pg~.
14891-14894 (1987). Perforin i~ described in Henkart, et al., J.
Ex~. Med., 160: 7~ (1984), and in Podack, et al., J. EXP. Med., 160:695 (1984). The above article~ are hereby incorporated by reference.
The term ion channel-forming protein~ includes the basic strueture~ of the ion chan~el-forming proteins as well a~
analogue~ and derlvative~.
In accordance with another embodiment, the peptide~ or proteins of the pre~ent invention may be employed in combination with an ion having pharmacological properties for the purposes hereinabove deecribed.
An ion having pharmacolcgical properties i~ one which when introduced into a target cell, virus, or virally-infected cell, inhibit~ and/or prevent~ and/or de~troys the growth of the target cell, viru~, or virally-infected cell.
Such an ion havlng pharmacological propertie~ 18 one which in the ab~ence of an ion channel forming peptide or protein i~
unab}e to cro~s a natural or ~ynthetic lipid membrane; in particu~lar a céll membrane, in sufficient amounts to affect a cell adver~ely.
The peptlde or protein and ion having pharmacological propertlec may be administered a~ a ~ingle composltlon or in ~eparate compo~ltion#, and the ~ingle or ~eparate compo~itions may include ad~ltional materials, active~ and/or inactives, in addition to the peptide or protein and ion having pharmacological propertie~. A~ repre~entative example~ of ion~ having pharmacologlcal propertie~ which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, and ~ilver ion~.

: -: s SVBSTITUTE SHEET

... . .. . . . . ..

W092/22317 2 1 11~ 1~ PCT/US92/~U~3 .:
The peptide or protein and the ion having pharmacological properties, whether administered or prepared in a single composition or in ~eparate compositions, are employed in amounts effective to inhibit and/or prevent and/or destroy the growth of the target cell, virus, or virally-infected cell. In effect, the ion potentiates the action of the peptide or protein, i.e., the amount of ion is effective to reduce the minimum effective concentration of the peptide or protein for inhibiting growth or a target cell, virus, or virally-infected cell.
The ion having pharmacological properties, when used topically, i~ generally employed in a concentration of from 0.05%
to 2.0X. When u~ed systemically, the ion is generally employed in an amount of from 1 to 10 mg. per kg. of ho~t weight. Peptide or protein dosages may be within the ranges hereinabove de~cribed.
It is also to be understood that the peptide or protein and ion may be dolivered or admini~tered in different form~; for example, the ion may be admini~tered oraIly, while the peptide or protein may bo adminiJtered by IV or IP.
A~ repre~entative example~ of admini~tering the peptide or protein and ion for topical or local administration, the peptide or protein could be administered in an amount of-up to about 1%
weight to weight and the ion delivered in an amount of about 50mM
(about o.lX). Alternatively, the ion, in the form of a ~alt such as ~odium fluoride, could be admini~tered orally in conjunction with systemic administration of the peptide. For example, the peptide or protein may be administered IV or IP to achieve a serum do~e of 100 microgram~ per milliliter (10 milligrams per kilogram) in conjunction with an oral dose of ion, in particular, ~odium fluoride, of 10 meq per kilogram.
In accordance with another embodiment, the peptides or protein~ of the present invention may be administered to a host in combination with an antibiotic selected from the cla~s cons~ting of bacitracins, gramacidin, polymyxin, vancomycin, ., ~
~: : SUBSTITUTE StlEET

,, ~~ WO92/22317 2 1 .1 1~ 1~37 PCT/US92/~03 teichoplanin, aminoglycosides, hydrophobic antibiotics, penicillins, monobactams, or derivatives or analogues thereof.
The bacitracins, gramacidin, polymyxin, vancomycin, and teichoplanin, and derivatives and analogues thereof, are a group of polypeptide antibiotics. A preferred bacitracin is bacitracin A.
Aminoglycoside antibiotics include to~ramycin, kanamycin, amikacin, the gentamicin~ (e.~., gentamicin Cl, gentamicin C2, gentamicin C1a), netilmicin, kanamycin, and derivatives and analogue~ thereof. The pr~ferred aminoglycosides are tobramycin and the gentamicin~. The aminoglycoside~, and the bacitracins hereinabove de~cribed, tend to be hydrophilic and water-soluble.
Penicillin~ which may be employed include, but are not limited to benzyl penicill~n, ampicillin, methicillin ~dimethoxyphenyl penicillin), ticaricillin, penicillin V
(phenoxymethyl penicillin), oxacillin, cloxacillin, diclo~acillin, flucloxacillin, amoxicillin, and amidinocillin.
Preferred penicillin~ which may be employed are benzyl penicillin and ampicillin. A preferred monobactam which may be employed is aztreonam.
A~ repre~entative example~ of hydrophobic antibiotics which may be used in the present invention, theré may ~e mentioned macrolides such a~ erythromycin, roxythromycin, clarithromycin~
etc.; 9-N-al~yl derivative~ of erythromycin; midecamycin acetate;
azithromycin; flurithromycin; rifabutin; rokitamycin; a 6-0-methyl erythromyci~ A known as.TE-031 (Tai~ho~; rifapentine;
benzypiperazinyl rifamycin~ ~uch as CGP-7040, CGP-5909, CGP-2793~3 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the Cll/C12 position of a macrolide ring known as A-62514 (Abbott); AC-7230 (Toyo Jozo);
bbYenzoxazinorifamycin; d~fficidin; dir~thromycin; a

3-N-piperdinomethylzaino methyl rifamycin SV known as FCE-2~250 (Farmitalia); M-119-a (Kirin Brewery); a 6-0-methyl-1-4n-~-carbamoyl erythromycin known a~ A-63075 : ~ SUBSTITUTE SHEET

~ 21l1~1'1 W09~2~17 PCT/US92/~U~3 (Abbott); 3-formylrifamyCin SV-hydrazones with diazabicycloalkyl side chains such as CGP-27557 and CGP-2986 (Ciba-Geigy); and 16-membered macrolides having a 3-0-alpha-L-cladinosyl moiety, such as 3-0-alpha-L-cladinosyldeepoxy rosaramicin; tylo~ins and acyl demycinosyl tylosins.
In addition to the macrolides hereinabove described, rifamycin, carbenicillin, and nafcillin may be employed as well.
Other antibiotics which may be used (whether or not hydrophobic) are antibiotics which are 50-S ribosome inhibitors such as lincomycin; clindamycin; and chloramphenicol; etc.;
antibiotics which have a large lipid like lactone ring, such as mystatin; pimaricin, etc.
The peptide or protein and antibiotic may be adminstered by direct administration to a target cell or by systemic or topical administration to a host which includes the target cell, in order to prevent, destroy or inhibit the growth of a target cell.
Target cells whosc growth may be prevented, inhibited, or destroyed by the admini~tration of the peptides and antibiotic include Gram-pos~tive and Gram-negative bacteria as well as fungal cell8.
The antibiotic, such as tho~e hereinabove described, or derivatives or analogues thereof, when used topically, i8 generally employed in a concetration of about 0.1X to about 10%.
When used ~y~temically, the antibiotic or derivative or analogue thereof i8 generally employed in an amount of from 1.25 mg. to about 4~ mg. per kg. of ho~t weight per day. Peptide or protein dosage~ may-be thos~ as hereinabove described.
A~ representative exmples of administering the peptide or protein and antibiotic for topical or local administration, the peptide or protein could be administered in an amount of from about 0.1X to about 10% weight to weight, and the antibiotic is delivered in an amount of from about 0.1% to about 10% weight to weight.

,:
~, , SUBSTITUTE SHEEt :: :

wo g2~22317 2 1 1 1 2 1 ~ PCT/US92/~03 In accordance with another emb~diment, the peptides or proteins of the present invention may be administered in combination with an antiparasitic agent or an antifungal agent.
Antiparasitic agents which may ~e employed include, but are not limited to, anti-protozoan agents. Examples of specific anti-parasitic agents which may be employed include, but are not limited to, pentamidine isethionate, and propamidine isethionate (Brolene).
Anti-fungal agents which may be employed include, but are not limited to, ketoconazole. It is also to be understood that certain anti-parasitic agents, may also have anti-fungal activity, and that certain anti-fungal agents may have anti-parasitic activity.
In accordance with another em~odiment, the peptides or proteins of the present inv~ntion may be administered in combination with an antibiotic which inhibits DNA gyrase, which is an enzyme involved in the formation of bond~ between individual co~ling strands of replicating bacterial DNA. Thus, DNA gyraJe i~ n~ce~sary for the normal replication of bacterial DNA, and, therefore, antibiotics which inhibit DNA gyra~e inhibit the normal replication of bacterial DNA.
Example~ of antlbiotics which inhibit DNA ~yra~e include nalidixic acid, oxolinic acid, cinoxacin, and quinolone antibiotics which include ciprofloxacin, no_floxacin, ofloxaain, enoxacin, pefloxacin, lomefloxacin, fleroxacin, tosul~loxacin, temafloxacin, and rufloxaci~.
In accordance with another embodiment, the peptides-or proteins of the present invention may be administered for the purpo~es hereinabove described in combination with one another.
The ~nYention will now be further ~escribed with respect to the following ~xample~; however, the scope of the present invention i~ not to be limited thereby.
Exam~le 1 - Antibacterial A~ay S~IBSTITUTE SHEET

21112i~ ~
WOg2/22317 PCT/US92/~#~3 The procedure for the followin~ antibacterial as~ay is ba~ed upon the guideline~ of the National Committee for Clinical Laboratory Standards, Document M7-T2, Volume 8, No. 8, 1988.
Stock ~olutions of the following Peptide~ 1, 2, and 3 are prepared at a concentration of 512 ~g/ml in sterile deionized distilled water and stored at -70C.
Peptide 1 has the following structural formula:
(SEQ ID N0:27)-NHCH2CH20H.
Peptide 2 has the following structural formula:
(SEQ ID N0:27)-NHCH2CH2NH2, Peptide 3 ha~ the following struetural formula:
(SEQ ID NO:27~-NH2.
The stock peptide solution iQ diluted in serial dilutions (1:2) down the wells of a microtiter plate so that the final ~- concentrations of peptides in the well~ are 0.25, 0.50, 1, 2, 4, 8, 16, 32, 64, 128, and 256 ~g/ml. 1-5 X 105 CFUs/ml of either 5. aureus A~CC 25923, E, coli ATCC 25922, or P. aeruainosa ATCC
27853 were added to the wells in full strength Mueller Hinton broth (BBL 114433 from a mid-log culture. The inoculum is ~tandarized ~peetrophotometrically at 600nm and is verified by colony counts. The plates are incubated for 16-20 hours at 37C, and the minimal inhibitory concentration (MIC) fo~ each peptide i~ determined. Minimal inhibitory concentration is defined as the lowest eoncentration of peptide which produces a clear werl in the microtiter plate. The re~ults are given in Table I below.
For purposes of explanation of Table I below, S is the MIC
of the peptide against S.aureus, P i~ the MIC of the peptide against P.aeruainosa, and E is the MIC of the peptide against E.coli.
TABLE I
Pe~tide MIC (uq~ml~
S P E
1 4,8 32 4 2 16 64,128 4 3 1~ 64,128 4 SUBSTITUTE SHEET

~ -~-~W092/2~17 2 ~ - PCT/USg2/~U~3 The above results indicate that a biologically active peptide having a C-terminal ethanolamine group provided increased biological activity as opposed to the same peptide having an unsubstituted C-terminal amide.
The peptides or proteins of the present invention, whether admini~tered alone or in combination with agents ~uch as toxic ions, antibotics, or other biologically active peptides or protein~ as hereinabove de~cribed, may be employed in a wide variety of pharmaceutical compo~ition~ in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or phyJiological saline ~olution. Such pharmac~utical compositions may be used topically or sy~temically and may be in any ~uitable form such a~ a liguid, ~olid, ~emi-solid, in~ectable solution, tablet, ointment, lotion, paste, `- capsule or the like. The peptide or protein and/or agent as hereinabove described may also be used in combination with ad~uvant~, protea~e inhibitors, or compatible drug~ whero such a combination i~ ~een to be de~irable or advantageous in controlling infection caused by harmful microorgani~ms including protozoa, viru~es, parasites, f~ungi, and the like.
The peptide or protein may be administerd to a ho~t in particular an animal, in an effective antibiotic and/or anti-tumor and/or antiviral and/or antimicrobial and/or anti~permicidal and/or antiungal and/or antiparasitic amount, or in an amount effective to stimulate wound heallng in a host. The peptides or proteins may be admin$~terd either alone or in combination with an ion having pharmacological propertie~, antibiotic, or ion channel forming peptide or protein as hereinabove de~cribed. When the peptide or protein is admini~tered in combination with an ion havinq pharmacolo~ical propertie~, the activity of the peptide or protein i8 potentiated.
When the peptide or protein i8 admini~tered in combination with an agent as hereinabove described, it i~ possible to , .

~: SUBSTITUTE SHEET

wog2/223l7 i.~ll2i~ PCT/USg2/~U~31~

.
administer the peptide or protein and agent in separate forms.
For example, the agent may be administered systemically and the peptide or protein may be administered topically.
When the peptide or protein is adminitered topically, it may be administered in combination with a water-soluble vehicle, said water-soluble vehicle being in the form of an ointment, cream, lotion, paste or the like. Examples of water-soluble vehicles which may be employed include, but are not limlted to, glycols, such as polyethylene glycol, hydroxycellulo~e, and KY Jelly. The water-soluble vehicle i~ preferably free of an oily substance.
The peptide or protein may al~o be employed in combination with a toxic ion a~ hereinabove de~cribed in the form of an oral composition for oral hygiene. Such a composition may be incorporated into a wide variety of compositions and materials used for oral hygiene purpo~es, which include, but are not limited to, toothpastes, mouthwa~hes, tooth gels, and tooth powders. Such composition may thus be used to treat or prevent periodontal di~ea~e, to prevent or reduce plaque, and/or to prevent or treat or reduce dental caric~. The peptide or protein and toxic ion may be used to inhibit, prevent, or destroy the growth of StrePtococcu~ mutan~, which i~ as~ociated with dental caries and periodontal disea~e.
Numerous modification~ and variations of the pre~ent invention are po~sible in light of the above teaching~ and, therefore, within the scope of the accompanying claims, the invention may be practiced other than a~ particularly de~cribed.
.

, ~:

SUBSTITUTE SHEET

-`~W092/22317 43 2t.1.`~7~ PCT/US92/04~3 SEQUENCE LISTING

(1) GENERAL INFORMATION:
(i) APPLICANT: Kari, U. Prasad Maloy, W. Lee (ii) TIT~E OF INVENTION: Compo~ition and Treatment with .
Biologically Active Peptide~ Having C-Terminal Substitutions (iii) NUMBER OF SEQUENCES: 113 (iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: Carella, Byrne, Bain, Gilfillan, Cecchi & Stewart (B) STREET: 6 Becker Earm Road (C) CITY: Ro~eland ~`
(D) STATE: New Jersey (E) COVNTRY: USA
(F) ZIP: 07068 ~ .
(v) COMPUTER READABLE FORM:
(A~ D IUM m E: 3.5 in~h diskette (B) COMPUTER: IBM PS/2 (C) OPERATING SYSTEM: PC-DOS
(D) SOFTWARE: DW4.V2 (vi) CURRENT APPLICATION DATA:
(A) APPLICATION NUMBER: 07713716 ~B) FILING DATE: 12-JUN-l99l (C) CLASSIFICATION:

SUBSTITUTE SHEET
.

WO92/2~17 PCT/US92/~Un3~
~11121~ ~44~

(vii) PRIOR APPLICATION DATA~
(A) APPLICATION NUMBER:
(B) FILING DATE:

(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Ol~tein, Elliot M. :~
(B) ~EGISTRATION NUMBER: 24,025 (C) REFERENOE /DOCKET NUMBER: 421250-119 (ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 201-994-1700 ;
(8) TELEFAX: 201-994-1744 - (2) IMFORM`ATION FOR SEQ ID NO:l:
(i) SEQUn~NCE CHARACTERISTICS
(A) LENGTH:. 20 a~ino acids (B) TYPE: amino acid ' ( C ) S~NDEDN~SS:
(D) TOPOLOGY: linear: ~.
,:
(ii) MOLECULE TYPE: pcptid~

~ (x) PUBLICATION INFORMATION:
:~ (H) DOCUMENT NUM~ER: W089/11290 ' .
(I) FILING DATE: l9-MAY-1989 (J) PUBLICATION DATE: 30-NOV-19~9 ; (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:
Ala Phe Ser Ly~ Ala Phe Ser Ly9 Ala Phe Ser Ly~ Als Phe Ser Lys Ala Phe Ser Lys (2) INFORMATIO~ FOR SEQ ID NO:2:

r, ~ . ~ SUBSTITUTE SHEET

'r~ W092/22317 PCl`/US92/04603 2l:~124l ~-(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 24 amino acids (B) TYPE: amino acid ~.
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (x) PUBLICATION INFO~MATION:
(H) DOCUMENT NUMBER: W089/11290 (I) FILING DATE: l9-MAY-1989 ~;
(J) PU~LICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO-2:
~~. Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe ~er Lys Ala Phe Ser LYB Ala Phe Ser Ly~

Ala Phe Ser Ly~ ~-(2) INFORMATION FOR SEQ ID NO:3:
(i) SEQVENCE CHARACTERISTICS:
: (A) LENGTH: 16 amino acids (B) m E: amino acid (C) 5TRANDEDNESS:
(D~ TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (x) PUBLICATION INFORMATION:
(~)`DOCUMENT NUMBER: W089/11290 (I) FILING DATE: l9-MAY-1989 (J) PUBLICATION DATE: 30-NOV-1989 SUBSTITUTE SHEET

W09~2~nr 2 1 1`12 1 ~ PCT/US92/~U~3~ ~
-46- ::

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:
Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala .
.
(2~ INFORMATION FOR SEQ ID NO:4: ;
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 20 amino acids :
(B) TYPE: amino acid .
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLSCULE mE peptide . .
(x) PUBLICATION INFORMATION:
(H) DOCU~ENT NUM~ER: W089/11290 FILING DATE:: l9-MAY-1989 (J) P W LICATION DATE: 30-NOV-19~9 (xi) SEQVENCE DESCRIPTION: SEQ ID NO:4:
Ser Ly~ Al- Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Ly~ Ala Phe Ser Lys Ala Phe (2) INFORMATION FOR SEQ ID NO:5:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 16 amino acids (B) TYPE: amino acid , (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ~, .

':~" -::

SIIBSTITUTE SHEET
.

,, - :

2 ~
W092/22317 PCT/~S92/04603 (x) PUBLICATION INFORMATION: .
(H) DOCUMENT NUMBER: W089/11290 :
(I) FILING DATE: 19-MAY-1989 (J) PUBLICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:
Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala ~he Ser Lys Ala Phe Ser (2) INFORMATION FOR SEQ ID NO:6:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 23 amino acids (B) m E: amino acid (C) S ~ EDNESS:
(D) TOPOLOGY: linear , (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: Ma~ainin I peptide.

(x) PUBLICATION INFORNATION:
(A) AUT~OR: Za~loff, Michael ~C) JOURNAL: Proc. Nat. _cad. Sci.
(D) VOLUME: 84 (F) PAGES: 5449-~453 (G) ~ATE: AUG - 1987 ~H~ DOCUMENT NUMBER: US 4810777 (I) FILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 , .

SUBSTITUTE SHEET

WO92~2~17 2 ~ Ll PCT/US92/~03`

( Y.i ) SEQUENCE DESCRIPTInN: SEQ ID NO:6 Gly Ile Gly Lys Phe Leu His ~er Ala Gly 5 l0 Lys Phe Gly Lys Ala Phe Val Gly Glu Ile l5 20 Met Lys Ser (2) IMFORMATION FOR SEQ ID ~10:7:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 23 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear ' (ii) MOLECULE TYPE: peptide (i.x) FEATURE:
: (A) NW~/KEY: Magainin II peptid~.

(x) PUBLICATION INEORMATION:
(A) AUTHOR: Za~loff, Michael (C) JOURNAL: .Proc. Nat. Acad. Sci.
tD) VOLUME: 84 (F) PAGES: 5449-5453 ' ~G~ DATE: AUG - 1987 (H) DOCUMENT NNMBER: US 4810777 (I) FILING DATE: 04-MAR-1987 (J) PU~LICATION DATE: 07-MAR-1989 SUBSTITUTE SHEET

211~2~ 4 .IWO92/2~17 PCT/US92/~U~3 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7 Gly Ile Gly Lys Phe Leu His Ser Ala Lys S 10 ,-Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met A~n Ser (2) INEORMATION FOR SEQ ID NO:8:
(i) SEQUENCE CHARACTERISTICS ~-(A) LENGTH: 22 amino acids (B) TYPE: amino acid :
(C) STRANDEDNESS:
(D)~TOPOLOGY: lin~ar .
(il) NOLECULE TYPE: peptide (ix) ~ URE:
;: (A) NAME/KEY: Magainin III peptide.
'.
(x~ PUBLICATION INFORMATION:
(A) AUTHOR: Za~loff, MlchaeI
() JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84 (F) PAOE 5: 5*49-5453 (G) DATE: AUG - 1987 (H) DOCUMENT NUMBER: US 4810777 (I) FI~ING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 ' ~J~
, ..:, SUBSTITUTE SHEET

. ~ -, ~ , .. ~ ~ ~ . .. . .

WO 92/22317 21~ ~ 2 ~ Ll PCI`/US92/W603~

( xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 8 Gly Ile Gly Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met Asn (2 ) INFORMATION FOR SEQ ID NO: 9:
( i ) SEQUENCE CHMACTERISTICS
(A) LENGT~: 22 amino acids ( B ) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear ( ii ) MOLECULE mE: peptide (ix) FEATURE:
(A) NAME/XEY: magainin peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zaslof, Michael ( C ) JOURNAL: Proc . Nat. Acad. Sci.
( D ) VOLUME: 84 (F) PAGES: 5449-5453 (G) DATE: AUG - 1987 (H) DOCUr~T NUMBER: US 4810777 (I) FILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 SUBSTITUTE SHEET

~ .

~iWO92/2~17 211 12 14 PCT/USg2/~3 (xi) SEQUENCE DESCRIE7TION: SEQ I D NO:9:
Ile Gly Ly~ Phe Leu His Ser Ala Lys Lys :
5 10 ' :
Phe Gly Lys Ala Phe Val Gly Glu Ile Met :~
A~n Ser , (2) INFORMATION FOR SEQ ID NO:10: .
(i) SEQUENCE CHARACTERISTICS , ~.
(A) LE~7GTH: 21 amino acids :
(B) TYPE: amino a~id (C) STRANDEDNESS:
(D) TOPOLOGY: linear , ~
(ii) MOLECULE TYPE: peptide ( iX ) FE;A$UR~:
(A) NAME~KEY: magainin peptide.

(x) PUBLICATION INFORMATION:
: (A)~ AUTHOR: Zasloff, Michael - ~ (C) JOU~NAL: Proc. Nat. Acad. Sci.
- (D) VOLUME: 84 (F) PAGES: 5449-5453 (G) 9ATE: AUG ~ 1987 (H) DOCUMENT NUMBER: US 4810777 (I) EILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 , ~ , , SUBSTITUTE SHEET
, , ., `~ ,~, .

W092J22317 2 1 1 1 2 1 4 PCT/US92/~U~3''`.

~xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:
Gly Lys Phe Leu His Ser Ala Lys Lys Phe S 10 ' '' Gly Lys Ala Phe Val Gly Glu Ile Met Asn 15 `. 20 Ser (2) INFORMATION FOR SEQ ID NO~
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide - (ix) EEATURE:
~: (A) NWME/KEY: magainin peptide.

(x) PUBLICATION INFORMATION: ~:
(A) AUTHOR: Zasloff:, Michael (G) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84 (F) PAGES: 5449-5453 (G) DATE: AUG - 1987 (H) DOCUMENT NUMBER: US 4810777 (I) FILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 . (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:
Lys Phe Leu Hi~ Ser Ala Ly~ Ly~ Phe Gly ~ 5 10 : Ly~ Ala Phe Val Gly Glu Ile Met Asn Ser , .

SUBSTITUTE ~SHEET
, . ,. ~

s~ . wog2/223l7 2 1 1 1 2 1~ . PCT/US92/~03 -.:~
(2) INFORMATION FOR SEQ ID NO:12~
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ; (ix) FEATURE:
(A) NAME/KEY: PGLa peptide.

(x) PUBLICATION INFORMATION: -- (A) AUTHOR: Hoffman, et al.
(C) JOURNAL: EMBO J.
(D) VOLUME: 2 ~(F) ~PAGES: 711-714 ~-~ (G) DATE: 1983 (A) AUTHOR: Andr-u, et al.
(C) JOURNAL: Journal of Biochemi~trY
(D) VOLUME: 149 (F) ~-PAGES: 531-S35 (G:) DATE: 1985 (A) AU~8OR: Gib~on, et al.
(C) JOURNAL: J. B~ol. Chem.
(D) VOLUME: 2~1 (F) PAGES: 5341-5349 : (G) DATE: 1986 :- (A) AUTHOR: Giovannini, et al.
(C) JOURNAL: Biochem J.
(D) ! VOLUME: 243 : (F) PAGES: 113-120 (G) DATE: 1987 SUBSTITUTE SHEET

WOg~2Z317 '~ PCT/US92/~3`

(xi) SEQUENCE DESCRIPTION: SE(2 ID N~:12: ;
Gly Met Ala Ser Lys Ala Gly Ala ILe Ala Gly Lyæ Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID MO:13:
(i) SEQUENCE CHARACTERI~TICS
(A) LENGTH: 25 amino acids (B) TYPE: amino acid (C) STRAND3DNESS:
(D~ TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: :
(A) NAME/XEY: XPF p~ptide.

(x) PUB~ICATION INFORMATION:
(A) AUTHOR: Hoffman, et al.l (C) JOURNAL: EMBO J.
(D) VOhUME: 2 (F) PAGES: 711-714 (G) DATE: 1983 (A~ AUTHOR: Andreu, et al.
(C) JOURNAL: Journal of Biochemi~trY
(D) VOLUME: l~9 (F) PAOE S: 531-535 (G) DATE: 1985 (A) AUTHOR: Gib~on, et al.
(C) JOURNAL: J. Biol. Chem.
(~) VO~UME: 261 : ~ (F) PAGES: 5341-5349 SUBSTITUTE SHEET

W092/22317 211121 ll - PCT/USg2/~3 :

(G) DATE: 1986 (A) AUTHOR: Giovannini, et al.
(C) JOURNAL: Biochem J. :
(D) VOLUME: 243 .
(F) PAGES: 113-120 :
(G) DATE: 1987 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:
Gly Trp Ala Ser Lys Ile Gly Gln Thr Leu Gly Ly~ I le Ala Lys Val Gly Leu 1ys Glu Leu I le Gln Pro Ly~

(2) INFORMATION FOR SEQ ID NO:14:
(i) SEQUENCE CHARACTERISTICS ~;
(A) LENGTH: 27 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TO~OLOGY: lin~ar (ii) MOLECULE TYrE: peptide (ix) FEATURE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:
(A~ A~JTHOR: Richter, K.
Egger, R.
Krei l (C) JOURNAL: J. Blol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-36B0 :~ :

, i , .
SUBSTITUTE SHEET

W092/2~t7 2 1 ~ 1 2 1 ~ PCT/US92/~3 -56- :

(G) DATE: 1986 (A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Re~earch _ _ .
(D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 198S
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-5349 (G) DATE: 1986 (H) DOCUMENT NUMBER: W090/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:
Gly Phe Gly Ser Phe Leu Gly Leu Ala Leu Lys Ala Ala Leu Ly~ Ile Gly Ala Asn Ala ' lS 20 Leu Gly Gly Ala Pro ~ln Gln (2) INFORMATION FOR SEQ ID NO:15:
(~) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear ' ~

,~" ,:
, :
-~ SUBS~ITUTE SHEET
, . .

'~,W092/2~17 _57_ PCr/US92/~3 (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K
Egger, R. ;:
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AUTHOR: Wakabaya8hi, T.
Kato, H.
~ Tachibaba, S.
;~ ~ (C) JOURNAL: Nucleic AcidY ~e~earch (D)~ VOLUME- 13 :
~-~ . (F) ~PAGES- 1817-1828 (G): DATE: 1985 :
: (A) AUTHOR: Gib-on, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: S341-5349 (G) DATE: 1986 : (H) DOCUMENT NUMBER: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

SUBSTITUTE SHEET

WO 92~22317 2 1 1 1 2 1 ~1 PCI`/US92/0460~ ~ `

( xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 15:
Gly Leu Ala Ser Phe Leu Gly Lys ALa Leu Lys Ala Gly Leu Lys Ile Gly Ala His Leu Leu Gly Gly Ala Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:16:
(i) SEQUENCE CBARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: am~no acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: pcptide (ix) FEATURE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:
~ (A) AUTHOR: Richter, K.
: Egger, R.
Kreil ' (C) JOURNAL: J. Biol. Chem.
(D~ VOL~: 261 (F~ PA OE S: 3676-3680 (G) DATE: 1986 (A) AUT~OR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research (D) VOLUME: 13 (F) PAGES: 1817-1828 , .
:
SUBSTITUTE SHEET

~WO92/2~17 211~2 ~ 4 PCT/USg2/~U~3 (G) DATE: 1985 (A) AulhOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-5349 (G) DATE: 1986 (H) DOCVMENT NUMBER: W090/04407 (I) FILING DATE: 16-OCT-19~9 (J) PUBLICATION DATE: 03-MAY-1990 I`
, (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:
Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu ,;:- . S' ~0 Lys Ala Gly Leu Lys Ile Gly Thr His Phe L-u Gly~Gly Ala Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:17:
~-~ (i) SEQUENCE CHARACTERISTICS
(A) LENGTH. 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
- (A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

., :
3, ~
S . . :, ` ~ !;

SUBSTITUTE SHEET

wo ~ 1 1 1 2 1 4 PCT/US92/~03 (A) AUTHOR: Richter, K.
Egger, RO
Kreil (C) JOURNA~: J. Biol. Chem.
~D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Re~earch (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 1985 (A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-53~9 ( G ) DATE: 1986 (~) DOCUMENT NUMBER: W090~04407 (I) FILING DATE: 16-OCT~1989 (J) PUBLICATION DATE: 03-MAY-l99O

(xi~ SEQUENCE DESCRIPTION: SEQ ID NO:17:
Gly Leu Ala 5er Leu L~u Gly Lys Ala Leu Lys Ala Thr Leu Ly~ Ile Gly Thr His Phe Leu Gly Gly Ala Pro Gln Gln SUBSTITUTE SHEET

211~21~i ;W092/22317 PCT/US92/~ ~3 (2) INFORMATION FOR SEQ ID NO:18:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATVRE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
' Egqer, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 19~6 (A) AUTHOR: Wakabayashi, T.
- Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Re~earch (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 1985 (A) AUTHOR: G~bson, B.W.
Poulter, L.
Williams, D.H.
` ! Maggio, J.E.

(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-5349 , :~::~ :
' '~; ~ .
SVBSTITUTE SHEET

W092~223172 ~ ~ 1 2 1 4 -62- PCT/US92/~U~3 "

(G) DATE: 1986 (H) DOCUMENT NUMBER: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:
Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Ly~ Ile Gly Ala Asn Met Leu Gly Gly Thr Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:l9:
(i) SEQUENCE CHARACTERISTICS
(A) LEWGTH: 27 amino acid~
- (~) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear ~: (i1) MOLEC~LE TYPE: peptide (ix) FEATURE:
(A) NAME~KEY: CPF peptid~.

(x) ~UBLIC~TION INFORMA~ION:
(A) AVTHOR: R~chter, K.
Egger, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 : (A) AUTHOR: Wakabaya~hi, T.
; ~

SUBSTITUTE SHEET
~ .

211121~ :
`W092r22317 PCT~US92~04~3 Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Re3ear~h (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 1985 (A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-5349 (G) DATE: 1986 '- (H) DOCUMENT NUMBER: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:
Gly Phe Gly Ser Phe Leu Gly Ly~ Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Aqn Ala Leu Gly Gly Ala Pro Gln Gln (2) INEORM~TION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS
(A) LENGT~: 27 ami~o acids (B) TYPE: amino acid (C3 STRANDEDNESS:

(D) TOPOLOGY: linear (ii) MOLECDIE L~E: peptide SUBSTITUTE SHEET

W092/2~17 2 1 1 1~ 1~ PCT/US92/nU~3''`~

(ix) FEATURE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-3680 (G) D~TE: 1986 (A) AUTHOR: Wakabaya~hi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: N~cleic Acids Research (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATEi 1985 (~) AUTHOR: Gib~on, B.W.
Poul~er, L.
Williams, D.H.
. Maggio, J.E.
- (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-5349 (G) DATE: 1986 ~H) DOCUNENT NUMBER: W090/04407 (I) FILING DATE: 16-OCT-1989 tJ) PUBLICATION DATE: 03-MAY-l99O

- SUBSTITUTE SHEET

:, ~

~ WO92/2~17 2 1 1 1 2 1 4 -65- PCT/US92/~U~3 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:
Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ser Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:21:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (8) TYPE: amino acid ( C ) STRANDED~ESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) E13ATURE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:
-~ (A) AUTHOR: Richter, K.
Egger, R.
Kreil ' (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AUT~OR: Wakabaya~hi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Re~earch (D) VOLUME: 13 (F) PACES: 1-17-1~2a - :, ~ ~ ~ SUBSTITUTE SHEET

::

W092~2~17 2 1 1 i % 1 ~1 -66- PCT/US92/~U~3,~

(G) DATE: 1985 (A) AUTHOR: G.ibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 .
(F) PAGES: 5341-5349 (G) DATE: 1986 (H) DOCUMENT NUMBER: WO90,/04407 (I) FILING DATE: 16-OCT-l9~9 (J) PUB~ICATION DATE: 03-MAY-l99O

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:
Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala A~n Leu `
: lS 20 Leu Gly Gly Thr Pro Gln Gln (23 I~ORMATION FOR SEQ ID NO:22:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino actd (C) STRANDEDNESS:
(D) TOPOLOGY: lin~ar (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME~KEY: CPF peptide.

(X) PUBLICATION INFORMATION:

, ~ :
SOBSTITUTE SHEET

WO 92/22317 P~/US92/04603 ~l:L~2~ 67-(A) AUTHOR: Richter, K.
Egger, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOL~JME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AVTEIOR: Wakabaya~hi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucle$c Acids Re~earch (D) VOLU~: 13 (F) PAGES: 1817-1828 (G) DATE: 1985 (A) AUTEIOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
~: (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 5341-5349 (G) DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:
Gly Phe Ala Ser Phe Leu Gly Ly~ Ala Leu 1~
Lys Ala Ala Leu Ly~ Ile Gly ~la Asn Ala 1~ 20 Leu Gly Gly Ala Pro Gln Gln (2) INFORMATION EOR SEQ ID NO:23:
(i) SEQUENCE CHARACTERISTICS
(A) ~NGTH: 27 amino acids ;~

~ SUBSTITUTE SHEET

,:

WOg~ 21~ -6~- PCT/~Sg2/~U~3 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) EEATURE:
(A) NAM~/KEY: CPF peptide.

(x) PUBLICATION INFO~MATION:
(A) AUT~OR: Richter, K.
Egger, R.
Kreil :
(C) JOURNAL: J. Biol. Chem.
~- (D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AUTHOR: Wakabaya~hi, T.
Rato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic A~ids Re~earch (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 1985 ~-(A) AUTHOR: Gib~on, B.W.
Poulter, L.
Williams, D.H. -Maggio, J.E.
(C~ JOURNAL: J Biol. Chem.
(D) VOLUME: 251 .
(F) PAGES: 5341-5349 IG) DATE: 1986 :: SUBSTITUTE SHEET -WOg2/2~17 PCT/US92/~3 21i . 21~ -69-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:
Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Met lS 20 Leu Gly Gly Ala Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:24:
(i) SEQUENCE C~ARACIERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: CPE peptlde.

:: (x) PUBLICATION INFORMATI.ON:
(A) AVTHOR: Richter, K.
Egger, R.
Kreil (C) JOURNAL: J. 8~ol. Chem.
~D~ VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Re~ear~h (D) VOLUME: 13 (F) PAGES: 1817-i828 ' .
:
SUBSTITUTE SHEET

WO gZ/~2317 2 1 112 ~ d, PCr/US92/04603:
--7t)--'~

( G ) DATE: 19~5 (A) At~THOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Ma~gio, J . E .
( C ) JOURNAL: J . Bi o l . Chem .
(D) VOLI~ME: 261 ( F ) PAGES: 53 41-53 49 ~G) DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:
Gly Phe Gly Ser Phe Leu Gly Ly~ Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala ' - 15 20 L~su Gly Gly Ser Leu Gln Gln (2 ) INFORMATION FOR SEQ II: NO: 25:
( i ) SEQUE:NCE CHARACTERI STICS
(A) LENGT~: 27 amino acids (B) mE: asnino acid t c ) STRANDEDNESS:
(D) TOPOI.OGY: linear ( ii ) MOLECUI.E TYPE: peptide (ix) E'EATURE:
(A~ ~ME/KEY: CPF peptide.

( x ) PUBLICATION INFO~TION:
(A) AUTHOR: Richter, K.

Egger, R.
Krei 1 ` W092~22317 2 1 1 ~ 1 471- PCTtUS92/~603 (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 (F) PAGES: 3676-3680 (G) DATE: 1986 (A) AUTHOR: Wakabay.ashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 19~5 (A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Bi~ol. Chem.
(D) VOLUME: 261 (F) PAGES: 534.1-5349 (G) DATE: .19~6 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:
:~ Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lyq Ala Gly Leu Lys Ile Gly Thr Asn Phe Leu Gly Gly Ala Pro Gln Gln ~ 25 (2) INTORMATION FOR SEQ ID NO:26:
~i) SEQUENCE CHARACTERISTICS
- (A) LENGTH: 27 amino acids (B3 TYPE: amino acid (C) STRANDEDNESS:

., , ,. . .
SUBSTIT;JTE SHEET
,. ~ `
~, ,~, Z l ~ 12 ~L 1 W092t2;_ . PCT/USg2/~U~3 (D) TOPOLOGY: linear (ii) MOLECULE m E: peptide (ix) FEATURE:
(A) NAME/KEY: C~F peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K
Egger, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(~) VOLUME: 261 (F) PAGES: 3676-3680 ' (G) DATE: 1986 (A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
~ (C) JOURNAL: Nucleic Acids Research : (D) VOLUME: 13 (F) PAGES: 1817-1828 (G) DATE: 1985 (A) AUTHOR: Gibson, B.W.
Poulter, L. ' Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261 - ~F) PAGES: 5341-5349 (G) DATE: 1986 ~: ~ S~JBSTITUTE SHEET
. .
~ :
, -:

~~ WOg2/2~17 2 ~ PCT/US92/~603 ~'~ ~73-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:
Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ser Pro Gln GLn (2) INFORMATION FOR SEQ ID NO:27:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECU~E TYPE: peptide - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile ~. 15 20 : Ala (2) INFORM~TION FOR SEQ ID NO:28:
(i) SEQUENCE C~RACTERISTICS:
(A) LENGTH: 21 ami~o acids (B) TYPE: amino acid (C) STRA ~ EDNESS:
(D) TOPOLOGY: linear , (ii) MOL~CUL~ TYPE: peptide SUBSTITUTE SHEET
, ~

wo g21223 . 2 1 1 ~ 2~ PCT/US92/~ ~3'`

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:
Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly (2) INFORMATION FOR SEQ ID NO:29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) mE amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear '- (ii) MOLECULE mE peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: .
Lys Ile Ala Gly Lys lle Gly Lys Ile Ala Gly Lys Ile Gly Lys Ile Ala Gly Lys Ile Gly (2) INFORMATION FOR SEQ ID NO:30: ' (i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) mE amino acid (C) STRAN~EDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE mE peptide SUBSTITUTE SHEET
~ . ~

~ -` WO92/2Z317 2 1 1 ~ ~ 1 4 PCT/US92/W603 .
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:
Lys Leu Ala Gly Lys Leu Ala Lys Leu Ala - Gly Lys Leu Ala Lys Leu Ala Gly Lys Leu Ala (2) INFORMATION FOR SEQ ID NO:31:
(i) SEQUENCE CHARACTERISTICS
(A) ~ENGT~: 21 amino acids (Bj TYPE: amino ac$d (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE ~ESCRIPTION: SEQ ID NO:31:
Lys Phe Ala Gly Ly~ Phe Ala Ly~ Phe Ala Gly Lys Phe Ala Ly~ Phe Ala Gly Lys Phe . ~
Ala (2) INFORMAT~ON FOR SEQ ID NO:32:
~i) SEQUENCE CHARACTERIST~CS
(A) LENGTH: 21 amino acids (B) m E: amino acid ( C ) STRANDE~NESS:
(D) TOPOLOGY: linear , (ii~ MOLECULE TYPE: pepti~e :, ,,, ~

SUBSTITUTE SHEET
,,. ~

.`-,::

WO92/22317 )1 :. 1 2 1 4 PCT/USg2/~603 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:
Lys Ala Leu Ser Lys Ala Leu Lys Ala Leu Ser Lys Ala Leu Lys Ala Leu Ser Lys Ala ~:
Leu ~.
(2) INFORMATION FOR SEQ ID NO:33:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids .
(B) TYPE: amino acid (C) STRA ~ EDNESS: '' (D) TOPOLOGY: l~near tii) MOLECULE m E: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:
Lys Leu Leu Ly~ Ala Leu Gly Lys Leu Leu S 10 "
Lys Ala Leu Gly Lys Leu Leu Ly~ Ala Leu 15 2~ . -Gly ~2) INFORMATION FOR SEQ ID NO:34:
(i) SEQUENCE CHARACTERISTICS
(A) LEMGT~: 21 amino acids (B) mE amino acid tc) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide '~. SUBSTITUTE SHEET

~;~

WO92/22317 211 12 1~1 _77_ PCT/U~92/~603 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:
Lys Ala Ile Gly Lys Ala Ile Lys Ala Ile Gly Lys Ala Ile Lys Ala Ile Gly Lys Ala Ile (2) INFORMATION FOR SEQ ID NO:35:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids - -(B) TYPE: amino acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:
Gly ~le Ala Ly~ Ile Ala Lys Gly Ile Ala ~0 Lys Ile Ala Lys Gly Ile Ala Ly~.Ile Ala Lys .
(2) INFORMATION FOR SEQ ID NO:36:
(i) SEQU%NCE CHARACTERISTICS
(A) LENGTH: 21 amino acid~
(B) T~PE: amino acid (C) STRANDEDNE5S:
(D) TO~OLOGY: linear (ii) MOLECULE TYPE: peptide :
' :' ~ ~ SUBSTITUTE SHEET
':~

WO92/2~17 PCT/USg2/~U~3 2 1 ~ 1 2 ~ ~- 78-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:
Lys Ile Ala Lys Ile Phe Gly Lys Ile Ala Lys Ile Phe Gly Lys I le Ala Lys Ile Phe Gly (2 ) INFORMATION FOR SEQ ID NO: 37: -( i ) SEQUENCE CHARACTERI STICS
( A ) LENGTEI: 21 amino acids -~;
( B ) mE: amino acid ( C ) STRA~EDNESS:
(D) TOPOLOGY: linear ~ . ( ii ) MOLECULE mE: peptide : ' ( xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 37:
Gly Ile Ala Arg I le Ala Ly~ Gly Ile Ala Arg T le Ala Lys Gly I le Ala Arq I le Ala : 15 20 Lys (2) INFORMATION FOR SEQ ID NO:38:
(i j SEQUENCE CHARACTERISTICS :
~A) LENGl~I: 21 amino acids (B) mE: amino acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear ( ii ) MOLECULE mE i peptide ,.. . .
~ ., SUBSTITUTE SHEET

`,, ~ ~ .: ~ .
, "

~111214 W092/22317 PCT/US92/~4~3 -79- .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:
Lys Phe Ala Arg Ile Ala Gly Lys Phe Ala Arg Ile Ala Gly Lys Phe Ala Arg Ile Ala Gly (2) INFORMATION FOR SEQ ID NO:39:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:
Gly Phe Ala Ly~ Ile Ala Lys Gly Phe Ala Lys Ile Ala Lys Gly Phe Ala Lys Ile Ala ; 15 2 Lys , .
~2) INFORMATION FOR.SEQ ID NO:40:
(i) SEQUENCE ~HARACTERISTICS
(A) LENGTH: 21 amino acids (8) TYPE: amino acid ~C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide tix) FEATURE:
~ (D) OTHER INFORMATION: Xaa is ornithine ,- ~ ' ..
SUBSTITUTE SHEET

WO92/22317 ~ PCT/US92/04603 '`~

(xi) SEQUENCE DESCRIPTION: SE~ ID NO:40:
Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile Ala (2) INFORMATION FOR SEQ ID NO:41:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l amino acids (B) mE amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: li~ear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:
Lys Ile Ala Arg Ile Ala Gly Lys Ile Ala 5 lO
Arg Ile Ala Gly Lys Ile Ala Arg Ile Ala l~ 20 Gly (2) INFORMATION FOR SEQ ID NO:4~:
(i) SEQUEN OE CH~RACTE~ISTICS
(A) LENGTH: 2l amino acids (B) TYPE: amino acid SC) STRANDE~NESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEA1URE:
(D) OTHER INFORMATION: Xaa is ornithine SUBSTITUTF ~;HEET

WO92/22317 2; :1 1,.,1~ PCT/US92/~U~3 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:
Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala Gly Lys $1e Ala Xaa Ile Ala Gly Lys Ile lS 20 Ala (2) INFORMATION FOR SEQ ID NO:43:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE m E: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:
Gly Ile Ala Arg Ile Phe Lys Gly Ile Ala S 10 ~ .
Arg Ile Phe Lys Gly Ile Ala Arg Ile Phe - Lys ~ ~ , (2) IMFORMATION FOR SEQ ID NO:44:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear -.

(ii) MOLECULE m E: peptide (ix) FEATURE:
(D) OT~ER INFORMATION: Xaa is norleucine : ' SUBSTITUTE SHEET
~ ~ `

W092~223t7 211121~ -82- PCT/US92/~U~3 -(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:
Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa Ala (2) INFORMATION FOR SEQ ID NO:45:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OT~ER INFORMATION: Xaa is norleucine (xi):SEQUENCE DESCRIPTION: SEQ $D NO:4S: I :
~ Lys Xaa Ala Gly Lys Ile Ala Ly~ Xaa Ala -~ : 5 10 : : ~Gly Lys Ile Ala Ly~ Xaa Ala Gly Lys Ile i lS 20 ;: Ala : (2) INFORMATION FOR SEQ ID NO:46:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acid~
(B) TYPE: amino acid (C) $TRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: poptide ,/j,~ ~

SUBSTITUTE SHEET

2il~21~
WO92/22317 PCTtUS92/~603 (ix) FEATURE:
(D) O'ln~R INEORMATION: Xaa is norleucine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:
Lys Ile Ala Gly Lys Xaa Ala Lys Ile ALa Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa l5 20 Ala (2) INFORMATION FOR SEQ ID NO:47:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
- (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATU~E:
(D) OTHER INFORMATION: Xaa is norvaline (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:
Lys Xaa Ala Gly Ly~ Xaa Ala Ly~ Xaa Ala Gly Lys Xaa Ala Ly~ Xaa Ala Gly Lys Xaa Ala (2) INFORMATION FOR SEQ ID NO:4B:
(i) SE~UENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid ( C ) STRANDEDNESS:

(D) TOPOLOGY: linear ;~

~ ~ SUBSTITUTE SHEET

wo92r22317 ~ 4- PCS/US92/~3 (ii) MOLECULE mE peptide (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norvaline (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4a Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala-Gly Lys Xaa Ala (2) INFORM~TION FOR SEQ ID NO:49:
(i) SEQ~ENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MO~ECULE TYPE: peptide (xi) SEQUENCE DESGRIPTION: SEQ ~D NO:49:
Lys Leu Leu Ser Ly~ Leu Gly Ly3 Leu Leu S 10 , Ser Lys Leu Gly Lys Leu Leu Ser Lys Leu Gly (2) IMFORMATION FOR SEQ ID NO:50:
~i) 5EQUENCE ~HARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
tD) TOPOLQGY: linear SUBSTITUTE SHEET

2;1:11%1~1 , ` WO 92/22317 PCI/US92/04603 --~5--( i i ) MOLECULE TYPE: peptide ( xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 50:
Lys Leu Leu Ser Lys Phe Gly Lys Leu Leu Ser Lys Ph~ Gly Ly~ Leu Leu Ser Lys Phe Gly (2 ) INFOR~ATION FO~ SEQ ID ~0: 5l:
( i ) SEQUENOE CEIARJ~ I STICS
(A) ~ENGTh: 21 a~ino acids (B ) TYPE: ~lno acld (C) STRA~EDNESS:
(D) TO~OLOGY: lin~ar ( ii ) MOr.ECULE TYPE: peptide ( ~x ) E~3ATURE: :
(D) OT~ER INFORM~TION: Xaa ~ J nonraline t xi ) SEQUENOE DESC~IPTION: SEQ ID NO: 5 l:
Ly~ Ile Ala Gly Ly~ Xaa Ala Ly~ Ile Ala S 10 ,, Gly Lys Xaa Ala Lys Il~ Ala Gly Ly~ Xaa Ala t 2 ) I~JFORMATION FO~ SEQ ID ~JO: 5;2:
( i ) SEQU~OE C~ARAC~E'RISTICS
(A) I,EN~ n: 21 amino ac~ds (B) ~YI?E: a~ino ac:id (C) ST~ANDEDNESS:
(D ) TOPOLOGY: llnear :~ .

SUBSTITUTE SHEET
. ~

WO92~22317 2 1~ 1% 1~ PCT/US92/~U~3 ' (ii) MOLECULE TYPE: peptide (xi) SEQUEN~E DESCRIPTION: SEQ ID NO:52:
His Ile Ala Gly His Ile Ala His Ile Ala Gly His Ile Ala His Ile Ala Gly His Ile Ala (2) INFORMATION FOR SEQ ID NO:53:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear -~

(ii) MOLECULE T~E: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:
Ala Gly Ly~ Ile Ala Ly~ I le Ala Gly Lys 5 10 :;
Ile Ala Ly~ I}e Ala Gly Lys Ile Ala Lys ' `;
Ile (23 INFORMATION FOR SEQ ID NO:54:
(i) SEQUENCE CHARACTSRISTICS
(A) LENGTH: 21 ami~o acids (B) TYPE: amino acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide . SUBSTITUTE SHEET

,~ ~

WO92t22317 ~ 2~ 4 ~ - PCT/US92/~U~3 -~7-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: :
Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly :
Lys :.
(2) INFORMATION FOR SEQ ID NO:55:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYYE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide , .
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:
Lys Ile Ala Gly Arg Ile Ala Ly~ Ile Ala `
Gly Ary Ile Ala Lys Ile Ala Gly Arg Ile Ala (2) INFORMATION FOR SEQ ID NO:56:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B3 TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear ;
(ii) MOLECULE TYPE: peptide , ~
,. ~
. .

SUBSTITUTE SHEET

WOg2/22317 h ~ 1 1 2 1 4 PCT/US92/~U~3.
-~a-~:i) SEQUENCE DESCRIPTION: SE:Q ID ~10: 56:
Arg I 1~ Ala Cly Arg Ile Ala Arg I 1~ Ala G'y Ar~ lle Ala Arg Ile Ala Gly Ar~ Ile lS 20 Ala ~ .

(2) INFORMATION FOR SEQ ID MO:57:
(i) SEQUENCE CE~RACTERISTICS
(A) LENGTH: ~.1 amino acids (B) m E: amino acid (C) STRANDEDNESS:
(D) TOPOLO~Y: linear (ii) MOLECULE TYPE- p-ptide ~xl) SEQUENCE DESCRIPTION: 3EQ ID NO:57:
Lys Val Ala Gly Lys Ile Ala I,y~ V~l Ala Gly Ly~ Ile Al- Ly- Val Ala Cly Ly~ Ile Ala:
"~
~: (2) INFORMA5ION FOR SEQ ID NO:5B:
(i) SEQUENCE CHARACTERISTICS
(A) LENG$H: 21 amino acids (B) m E: amino a~id (C) S~ANDEDNESS:
(D) TOPOLOGY: linear tii) MOLECULE m E: peptide : .

7~J'''~

SUBSTITUTE SHEET

~-~ wo g2/223l, 2 1 1 1 2 1~ PCT/US92/~03 (xi) SEQUENCE DESCRIPTIC)N: SEQ ID NO:~8:
Lys Ile Ala Gly Lys Val Ala Lys Ile Ala Gly Lys Val Ala Lys Ile Ala Cly Lys Val Ala (2) INFORMATION FOR SEQ ID ~10:59:
..
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:
A1a Ly~ $~e Ala Gly Ly~ Ile Ala Ly~ Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys lS 20 - I}e .

(2) INFORM~TION FOR SEQ ID MO:60: ,~
(i) SEQUENCE CHARACTERISTIC5 (A) LEN~Tn: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: lin~ar (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) O~HER I~FORMATION: Xaa is ornithine ,. ~
.~ :

~: - SUBSTITUTE SHEET

2 1'~
WO 92/22317 PCI~/US92/04603 ~

(xi) SEQUEN~E DESCRIPTION: SEQ ID NO:60:
Xaa I le Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa I le Ala Xaa Ile Ala Gly Xaa Ile Ala (2) INFORMATION FOR SEQ ID NO: 61:
( i ) SEQUENCE CHARACTERI STICS
(A) LENGTH: 21 amino acids ( B ) mE: amino acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear `~
- ( ii ) MOLECULE mE: peptide ( xi ) SEQUENCE DESCRIPTION: SEQ ID NO: 61:
Lys Phe Ala Gly Lys I le Ala Ly~ Phe Ala : 10 Gly Lys I le Ala Ly~ Phe Ala Gly Lys I le Ala (2 j INFORMATION FOR SEQ ID NO: 62: ( i ) SEQUENOE CH~RACTERISTICS
(A) IENGTH: 21 amino acids ( B ) mE: amino acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear ( ii ) MOLECUI.E mE: peptide ::

., ~, ,.,,.,, ~ ~ :
,,. i;;, ~

, , i . ~ , SUBSTITUTE SHEET

~i - ~, :, ~ WO92/22317 2 1 ~ 1 2 1 ~I PCT/US92/~3 ( Y.i ) SEQUENCE DESCRIPTION: SEQ ID NO:62:
Lys Il~! Ala Gly Lys Phe Ala I.ys Ile Ala :

Gly Lys Phe Ala Lys Ile Ala Gly Lys Phe Ala (2) INFORMATION FOR SE~ ID NO:63:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is cyclohexylalanine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:
Lys Xaa Ala Gly Ly~ Ile Ala Ly~ Xaa Ala Gly Lys Ile Aia Lys Xaa Ala Gly Lys Ile 15 20 , Ala (2) I~ORNATION FOR SEQ ID NO:64:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: ~1 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
~D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide SUBSTITUTE SHEET

W092/22317 ~ li 12 1 I PCT/US92/~3 (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:
Lys Xaa Ala Lys I le Ala Gly Lys Xaa Ala S 10 ,.
Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala l5 20 . .-Gly (2) INFORMATION FOR SEQ ID NO:65:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acids (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:
Arg Ile Ala Gly Lys Ile Ala Arg Ile` Ala Gly Lys Ile Ala Arg Ile Ala Gly Lys Ile l5 20 ' Ala (2) INFORMATION FOR SEQ ID NO:66:
(i~ SEQUENCE ~HARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE m E: peptide - ' `
~' ~

~ - ~ SUBSTITUTE SHEET

~ . .
WO g2/22317 2 1 ~ 1 % i ~1 93 ~~ PCT/VS92~603 (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is homoarginine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:
Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Ala (2)INFORMATION FOR SEQ ID NO:67:
(i) SEQUENCE CHARACTERISTICS:
(A) LEN~Th: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix~ FEATURE: Xaa i3 p-aminophenylalanine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:
Xaa Ile Ala Gly Ly~ Ile Ala Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile Ala (2) INFORMAT.ION FOR 5EQ ID NO:68:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid ~ (C) STRANDEDNESS:
; (D) TOPOLOGY: linear SUBSTITUTE SHEET

W092/2~ 2l~ PCTtUS92/~3 (ii) MOLECULRE TYPE: peptide (ix) FEATURE: Xaa is p-aminophenylalanine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6B:
Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile 15 . 20`
Ala (2) INFORMATION FOR SEQ ID NO:69:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 24 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPO~OGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:
Ly~ Ile Ala Ly~ Ile Ala Gly Lys Ile Ala ; S 10 Ly~ Ile Ala Gly Lys Ile Ala Lys Ile Ala 15 20 ' Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:70:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C3 STRANDEDNESS:
(D) TOPOLOGY: llnear (ii) MOLECULE TYPE: peptide :, ,~

~ ~ . SUE3STITUTE SHEET

~`- wo g2,2~.7 2 1 1 1 2 1 ~1 . PCT/US92/~U~3 _95 (xi) SEQUENCE DESCRIPTI~N: SEQ ID NO:/0:
Lys L~u Ala Ser Ly~ Ala Gly Lys Ile Ala Gly 5 ` 10 Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) IMFORMATION FOR SEQ ID ~l0:71:
(1) SEQUENCE CHARACTERISTICS
(A) LENGTH: ~1 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS:
ID) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFO~MATION: Xaa iq ornithine ~xi) SEoUENCE DESCRIPTION: SEQ ID NO:71:
Lys Il~ Ala Gly Ly~ Ile Ala Lys Ile Ala Gl~

Xaa Ile Ala Lys Ile Ala Gly Ly8 Ile A~a (2) INFORMATION FOR SEQ ID NO:72:
(i) SEQUENCE CHARACTERISTICS
~A) L~NGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear , ~ (ii) MOLECULE TYPE: peptide ,." .

SUBSTITUTE SHEET
: " ~

WO9~22317 2 1 1 1 2 1 ~ PCT/US92/~3.~ ;

. ~
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:
Lys Ile Ala Gly Lys Ile Ala ~ys Ile Ala 5 10 :
Gly Arg Ile Ala Ly~ Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:73~
(i) SEQUENCE CHARACTERISTI.CS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) FEATURE: ;
(D) OTHER INFORMATION: Xaa i~ norleucine.

: (xi)~ SEQUENCE DESCRIPTION: SEQ ID NO:73:
Ly~ Ile Ala Gly Lys Ile Ala Ly~ Ile Ala Gly X-a Ile Ala Lys Ile Ala Gly~Lys Ile ~:Ala : ~2) INFORMATION FOR SEQ ID NO:74:
- (i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acid~
-~ (B) TYPE: amino.acid (C) STRANDEDNESS:
(Dj TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ix) FEATURE: ~
(D)~OTHER~INFORMATION: Xaa is norvaline ": :
~,^,.-~, - ~
SUBSTITUTE SHEET

~ "~

! WO 92/22317 2 1 1 1 2 1~ PCT/US92/~K03 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:75:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids . -(B) m E: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) O'lnER INFORMATION: Xaa is ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:
Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala Gly Xaa Phe Ala Lys Phe Ala Gly Lys Ph~ Ala 15 20 ' (2) INFO~MATION FOR SEQ ID NO:76:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) m E: amino acid (C) STRANDEDNE5S:
(D) TOPOLOGY: linear (ii) MOLECULE m E: peptide : (ix) EE~TURE:

;~ SVBSTITUTE SHEET

W092/2~ / 2 1 1 1 2 1~ PCT/US92/~U~3 - ;
_9 (D) OTHER INFORMATION: Xaa is ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:
Lys Ile Ala Gly Lys Phe Ala Lys Ile Ala Gly Xaa Phe Ala Lys Ile Ala Gly Lys Phe ~.
15 20 ~ ~
Ala .`

(2) INFORMATION FOR SEQ ID NO:77: .;-(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids `
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE m E: peptide (ix) FEA=:
(D) OTHER INFORMATION: Xaa at re~idues 6, 13, and 20 : is norleucine, Xaa at - residue 12 is ornithi'ne `: :
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:
Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala Gly Xaa Xaa Ala Lys Ile Ala Gly Lys Xaa ~0 Ala .
(2) INFORMATION FOR SEQ ID NO:78:
(i) SEQUENCE CHARACT~RISTICS
(A) LENGTH: 21 amino acids (B) i~P~: amino acid ,,-;.: ~ , ,:

SUBS~ITUTE SHEET

,.. ,,, .~ .

~-- wog2/2~ PCT/US92/~U~3 (C) STRANDEDNESS: :
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:
Lys Met Ala Ser Lys Ala Gly Lys Ile Ala 5 lO
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:79:
(i.) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C1 STRANDEDNESS: :
(D) TOPOLOGY: linear ( ii ) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:
Lys Ile Ala Ser Lys Ala Gly Lys Ile Ala 10ly Lys lle Ala Lys Val Ala Leu Lys Ala Leu lS 20 (~) INFORMATION FOR SEQ ID NO:80:
(i) SEQUENCE CHAR~CTERISTICS
~A) LENGTH: 21 amino acids (Bj TYPE: amino acid (C) STRANDEDNESS:
~D) TOPOLOGY: linear ; ~ -~, ,, ~
, ~
SUBSTITUTE~ SHEET
,.,;.~ ~ . ~

WO g2/2~17 2 1 1 1 2 1 4 PCT/US92/~U~3 (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:
Ly~ I le Ala Ser Lys Ala Gly Ly~ Xaa Ala Gly Ly~ Ile Ala Ly~ Val Ala Leu Ly~ Ala Leu lS 20 (2) INFORMATION FOR SEQ ID NO:81:
(i) SEQUENCE CHARACTSRISTlCS
(A) LENG$H: 21 amino acid~
-(B) TYPE: amino acid (C) STRANDEDNESS:
-(D) TOPOLOGY: lin~ar ~ (ii) MOLECULE TYPE: peptide : ~(ix) FEATURE:
(D) OTh~R INFORMATION: Xaa is norleucine , ~ , (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:
Ly~ Leu Ala Ser Ly~ Ala Gly Lys Xaa Ala Gly Lys Ile Ala Ly~ Val Ala Leu Lys Ala Leu .
(2) INFORMATlON FOR SEQ ID NO:82:
(i) SEQUENCE CHARACTERISTICS
I (A) LENGTH: 21 amino acid~

~:
,.~ ; :

SUBSTITUTE SHEET

WO92~22317 211 21 ~ PCT/US92/ ~ 03 - 101- :

(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine (xi) SEQUENCE DESCRI~TION: SEQ ID NO:82:
Lys Xaa Ala Ser Lys Ala Gly Lys Xaa Ala Gly Lys Ile Ala Ly~ Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:~3:
ti) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide , ~
(ix3 FEATURE:
(D) OTHER INFORMATION: Xaa is p-aminophenylalanine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile ~0 Ala SUBSTITUTE SHEET

W092/2~17 2111~14 PCTJUS92/~K~3.

(2) INFORMATION FOR SEQ ID NO:84:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:
Lys ~le Ala Gly Ala Ile Ala Ly~ Ile Ala Gly Lys Ile Ala Ly~ Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:85:
~i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
; : (D) TO~OLO~Y: linear ~ .
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESC~IPTION: SEQ ID NO:85:
Lys I le Ala Gly Ly~ Ile Ala Lys Ile Ala Gly Ala Ile Ala Ly~ Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:86:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids ..~, SUBSTITUTE SHEET

-`~W092/2~17 2 1 ~ 1 2 1~103- PCT/USg2/~3 (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:
Lys Ile Ala Gly Ly~ Ile Ala Lys Ile Ala Gly Ly~ Ile Ala Lys Ile Ala Gly Ala Ile Ala (2) INFORMATION FOR SEQ ;D NO:87:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
:(D) TOPOLOGY: linear ~;:(ii) MOLECULE TYPE: peptide (xi) SEQUENOE DESCRIPTION: SEQ ID NO:87:
Lys Leu Ala Ser Lys Ala Ala Lys Ile Ala 5 1 0 ~
., ;:~ Ala Lys-Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:88:
(i) SEQUENCE CHARACTERISTICS:
(A) ~ENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TO~QLOGY: l~near ~ (ii) MOLEC~LE TYPE: peptide .: , ,, ^' ~'~, SUBSTITUTE SHEET

, ~

WOgt/22317 PCT/US92/~U~3~
?Jl~ ~21~ -104-(xi) SEQUENCE DESCRIPTION: SEQ I~ NO:~8:
Lys Ile Ala Lys Lys Ile Ala Lys Ile Ala S 10 ' Lys Lys Ile Ala Lys lle Ala Lys Lys Ile Ala (2) INFORNATION FOR SEQ ID NO:89:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids ::
(B) TYPE: amino acid (C) STRANDEDNESS: :.
(D) TOPOLOGY: linear '- (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:
Phe Ala Lys Lys Phe Ala Lys Phe Ala Lys Lys Phe Ala Lys Phe Ala Lys Lys Phe ~: Ala (2) INFORMATION FOR SEQ ID NO:90:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) S ~ EDNESS:
(~) TOPOLOGY: linear , (ii~ MOLECULE TYPE: pept~de , ~ . SUBSTITUTESHEET
:'''"; ~

.f-' W092/22317 2111214 lo~ PCT/US92/~U~3 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:
Lys Phe Ala Lys Lyq Ile Ala Lys Phe Ala Lys Lys Ile Ala Lys Phe Ala Lys Lys Ile lS 20 Ala (2) INFORMATION FOR SEQ ID NO:9l:
(i) SEQUENCE CHARACTERISTICS
(A) LEN~Tn: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9l:
Ala Ile Ala Gly Lyq Ile Ala Ly~ Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly ~ys Ile lS 20 Ala (2) INFORMATION EOR SEQ ID NO:92:
(i) SEQUENCE CHARACTERISTICS
(A) LEN~Th: 21 amino acids (B) TYPE: amino acid (C) STRA ~ EDNESS:
(D) TOPOLOGY: linear , (ii) MOLECULE TYPE: peptide SUBSTITUTE SHEET

WO Y~Z~3l7 ~ 2 1 g PCT/US92/~603~: ~

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:92: ::
Lys Ile Ala Gly Lys Ile Ala Ala Ile Ala S 10 . ., Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala (2) INFORMATIO~ FOR SEQ ID NO:93:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) m E: amino acid (~) STRANDED~IESS:
(D) TOPOLOGY: linear - (ii) MOLECULE TYPE: peptide . . .
(xi) 5EQUENCE DESCRIPTION: SEQ ID NO:93:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Ala Ile Ala Gly Lys Ile -Ala (2) INFORMATION FOR SEQ ID NO:94:
(i) SEQUENCE GHARACTERI5TICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNE5S
(D~ TOPOLOGY: linear .
(ii) MoT-T~cuLE m E: peptide .

~ ~ SlJBSTITUTE SHEET

WO92/2~17 'Z~ 1 1 2 1 4 PCT/US92/~03 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:
Gly Met Ala Ser Ly~ Ala Gly Lys Ile Ala Gly Lys Ile Ala Ly~ Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:95:
(~) SEQUENCE CHARACTERISTICS
(A) LENGTX: 11 amino acids (B) TYPE: amino acld (C) STRANDEDNESS:
(D) TO~OLOGY: linear (ii) MOLECULE TYPE: peptide (~i) SEQUENOE DESCRIPTION: SEQ ID NO:9S:
Leu LYJ Lys Leu Ly~ Lys Leu Leu Lys L~u Leu (2) INFORMATION FOR SEQ ID NO:96:
(i) SEQUENOE CHARACTERISTICS
(A) LENGTH: 12 amino acid~ .
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TO~OLOGY: linear (ii) MOLECULE TYPE: pept~de (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:
Leu Leu Ly~ Lys Leu Lys Lys Leu Leu Ly~
Leu Leu : SUBSTITUTE SHEET

wog2/2~17 2 1 ~ ~ 2 1 ~ -lo~- PCT/USg2/~U~3 ~2) INFORMATION FOR SEQ ID NO:97: :
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 13 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENOE DESCRIPTION: SEQ ID NO:97:
Lys Leu Leu LYJ Lys Leu Lys Ly~ Leu Leu -~

~y~ Leu Leu (2) INFORMATION FOR SEQ ID NO:9~:
(i) SEQUENCE CHARACTERISTICS
~:~ (A) LENGT~: 14 am~no ac~ds : (B) TYPE: a~no acid ~- ~ (C) STR~NESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide ~ ;

~: (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:
~: Lys Lys Le~ Leu Lys Lys Leu LYR Lys Leu S i0 - Leu Ly~ Leu LQU

(2) INEORMATION EOR SEQ ID NO:99-(i) SEQUENOE CHARACTERISTICS
(A~ LENGT~: 16!amino acids (B) TYæE: amino ac~d (C) STRANDEDNESS:
(D) TOPOLOGY: linear SUBSTITUTE SHEET
,, ~,~ ,, ~ ` :

~`~WOg2/22317 2; 1 1 2 1 ~ PCT/USg2/~3 (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:
Lys Lys Leu Leu Ly~ Ly~ Leu Ly~ Lys Leu Leu Lys Lys Leu Arg Arg (2) INFORMATION EOR SEQ ID NO:100:
(i) SEQUENOE C~ARACTERISTICS
(A) LENGT~: 16 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS: -(D) TOPO~OGY: linear (ii) MOLECU~E TYPE: peptide ) (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:
; ~ Lys Leu Ly- Lys Leu L~u Lys Lys Leu Ly~
`'' ~ S 10 , Ly~ Leu L~u Lys Leu Leu - ~ 15 , ~
(2~) :INFORMATION FOR SEQ ID NO:101:
. ,, ", ~ ~ . .
i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 amino acid~ .-(B) TYPE: amino acid .
(C) STRANDEDNESS:
- (D) TO~OLOGY: linear :: :
(ii) MOLECUIE TYPE: peptide ~; :
(xi) SEQUE~CE DESCRIPTION: SEQ ID NO:101:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys -~ Leu Leu Lys Lys-Asn SUBSTITUTE SHEET

21 . 121~ `
WOg2~22317 PCTtUS92/~3 -110- , (2) INFORMATION FOR SEQ ID NO:102:
(i) SEQUENCE CHARA OE RISTICS
(A) LENGTH: 15 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INEORMATION: xaa i~ homoserine.
.
(xi) SEQUENOE DESCRIPTION: SEQ ID NO:102:
L~u Ly~ Ly~ Leu Lcu LYJ Lys Leu Ly~ Lys L~u Leu Lys Ly~ Xaa (2) INFORMATION EOR SEQ ID NO:103:
(1) SEQUENCE C~ARACTERISTICS
(A) LENCI~: 18 umino acids (B) TYPE: a~ino acid ~: ~ (C) STR~n3SS: . .-(D) TOPO~OGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENC$ DESCRIPTION: SEQ ID NO:103:
Leu Lys Leu Leu Lys Lys Leu Leu Lys Ly~

Asn Lys Lys L~u Leu Ly~ Lys Leu ~2) INFO~MATION FOR SEQ ID NO:104:
(1) SEQUENCE C~ARACTERISTICS
:

SUBSTITUTE SHEET
.

- 2111~14 ~ WOg2/2231~ PCT/US92/04~3 (A) LENGTH: 18 amino acid~
(B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUE~ E DESCRIPTION: SEQ ID NO: 104:
Leu LYJ Leu Leu Lys Ly~ Leu Leu Lys Ly~
S 10 , Pro Ly~ Ly~ Leu Leu Ly~ Lys Leu ~
' :' .
- (2) INFORMATION FOR SEQ ID NO: 105:
( i ) SEQUENCE CElARACTERISTICS
(A) IENC~H: 22 a~ino acids ~ (B) mE: a~ino acid ~;
``' ~ (C) S~RAND~SS: .
~: (D) =)o~: lin~-r ( ii ) MOLECULE mE: peptide (xi)~ SEQUEN OE DESCRIPTION: SEQ rD N0105:
Leu Leu Lys Ly~ L~u Ly~ Lys Leu Leu Lys Ly~ Leu Gln Gly Pro Pro Gln Gly Gln Ser Pro Gln (2 ) $NEORMATION FOR SEQ $D NQ: 106:
( i ) SEQUE:~tOE CHARACT~;RISTICS
(A) LJ5NGl~: 20 amino acids ( 8 ) mE: amino acid ~ ~ (C) S~E~SS:
" ~

~", ~ , SUBSTITUTE SHEET

W092/22317 2 i ~ 1 2 1 ~ PCT/US92/~U~3':
-112- :

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (~i) SEQVENCE DESC~IPTION: SEQ ID NO:106:
Leu Ala Ser Lys Ala Gly Ala Ile Ala Gly Lys Ile Ala Lys Lys Leu Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:107:
(i) SEQUENCE CHARACT.ERISTICS
(A) LENGT~: 7 amino acid~
(B) TYPE: am~no acid ( C ) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENOE DESCRIPTION: SEQ ID NO:107:
Leu Lys Ly~ L~u Ly~ Ly~ Leu S

(2) INFORMATION FOR SEQ ID NO:108:
(~) SEQUENCE C~ARACTERISTICS
(A) ~ENGT~: 8 amino acid3 (B) TYPE: am~no acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear .
tii) MOLECULE TYPE: peptide (xl) SEQUENOE DESGRIPTION: SEQ ID NO:108:
Leu Leu LYJ Ly~ L-u Ly~ Lys Leu S

SUBSTITUTE SHEET

~, ~l L12~ -WOs2~2~17 PCT/US92/04603 (2) INFORMATION FOR SEQ ID NO:109:
(i) SEQUENCE CHARACT~RISTICS
(A) LENGT~: 9 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (li) MOLECULE TYPE: peptide : (~1) SEQUENOE DESCRIPTION: SEQ ID NO:109:
Ly~ Leu L~u Lys Ly~ L u Ly~ Lys Leu S

(2) INFORMATION FOR SEQ ID NO:llO:
'- (i) SEQUENCE C~ARACTERISTICS
(A) LENGT~: 10 amino acid~
(B) mE a~lno acid (C) ST~SS::
: (D) TOPOLOGY: lin~ar (ii) MOLECNLE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:llO:
~ Ly~ Lys L~u Leu Ly~ Lys Leu Lys Lys Leu '~ 5 10 (2~ INFORMATION FOR SEQ ID NO:lll:
(i) SEQUEN OE CHARACTERISTICS
~: (A) LENGTH: li amino acid~
(B) TYPE: am~no acid .
(C) STRANDEDNESS:
(D) TOPOLOGY: linear . ~

SUBSTITUTE SHEET

W092/2231~ 2 1 ~ 1 2 1 ~ PCT/USg2/~K~3 ~

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:lll:
Leu Lys Ly~ Leu Leu Ly~ Lys Leu r.ys Ly6 Leu (2) INFORMATION FOR SEQ ID NO:112:
(i) SEQUENCE CHARA~T~RISTICS
(A) LENGTH: 11 amino acid~
(B) TYPE: a~ino acid (C) STRANDEDNESS:
(D) TOPOLOGY: lin ar (ii) MO.LECULE TYPE: peptide .
(xi) SEQUENCE DESCRI~TION: SEQ ID NO:112:.
: Ala Ly~ Ly~ L~u Leu Ly~ Ly~ L~u Ly~ Ly~ Leu (2) INFORMATION FOR SEQ ID NO:113:
(i) SEQUENCE CRARACTERISTICS
(A) LENGTH: 14 a~ino ac~ds (B) TYPE: a~ino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (li) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTI~N: SEQ ID NO:113:
Leu Ly~ Ly~ Leu Leu Ly- Lys Leu Ly~ Ly~ Leu Leu Lys Arg , - S~JBSTITUTE SHEET

Claims (43)

WHAT IS CLAIMED IS:

1. A C-terminal substituted peptide or protein of the formula:

, wherein X is a biologically active amphiphilic peptide or protein, said peptide or protein being an ion channel-forming peptide or protein, and T is selected from the group consisting of:
(a) O-R, wherein R is a substituted or unsubstituted aliphatic, aromatic, or aralkyl group having from 1 to 10 carbon atoms;
(b) NH-NH2;
(c) NH-OH; and (d) , wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein group (i) is a hydroxy-substituted aliphatic, aromatic or aralkyl group having no more than 10 carbon atoms, and group (ii) is an amino-substituted aliphatic, aromatic, aralkyl, or alkylaromatic group. and at least one of R' and R" is group (i) or group (ii).

2. The peptide of Claim 1 wherein T is NH-CH2CH2-OH.

3. The peptide of Claim 1 wherein T is NH-CH2CH2-NH2.

4. The peptide of Claim 1 wherein X is a magainin peptide.

5. The peptide of Claim 1 wherein X is a PGLa peptide.

6. The peptide of Claim 1 wherein X is an XPF peptide.

7. The peptide of Claim 1 wherein X is a CPF peptide.

8. The peptide of Claim 1 wherein X is a cecropin.

9. The peptide of Claim 1 wherein X is a sarcotoxin.

10. The peptide of Claim 1 wherein X includes one of the following basic structures X31 through X37, wherein:
X31 is -[R31-R32-R32-R33-R31-R32-R32]n-;

X32 is -[R32-R32-R33-R31-R32-R32-R31]n-;
X33 is -[R32-R33-R31-R32-R32-R31-R32]n-;
X34 is -[R33-R31-R32-R32-R31-R32-R32]n-;
X35 is -[R31-R32-R32-R31-R32-R32-R33]n-;
X36 is -[R32-R32-R31-R32-R32-R33-R31]n-; and X37 is -[R32-R31-R32-R32-R33-R31-R32]n-, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.

11. The peptide of Claim 1 wherein X includes the following basic structure X40:

wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid.

12. The peptide of Claim 11 wherein X includes the following structure:
Y40-X40, wherein X40 is as hereinabove described in Claim 11, and Y40 is:
(i) R32-, or (ii) R32-R32-; or (iii) R34-R32-R32; or (iv) R33-R34-R32-R32; or (v) R32-R33-R34-R32-R32; or (vi) R32-R32-R33-R34-R32-R32; or (vii) R31-R32-R32-R33-R34-R32-R32.

13. The peptide of Claim 11 wherein X includes the following structure:
X40-Z40, wherein X40 is as hereinabove described in Claim 11, and Z40 is:
(i) R31-, or (ii) R31-R32-; or (iii) R31-R32-R32; or (iv) R31-R32-R32-R33; or (v) R31-R32-R32-R33-R34; or (vi) R31-R32-R32-R33-R34-R32; or (vii) R31-R32-R32-R33-R34-R32-R32.

14. The peptide of Claim 11 wherein X includes the following structure:
(Y40)a-X40-(Z40)b, wherein Y40 and Z40 are as previously defined in Claims 12 and 13, a is 0 or 1, and b is 0 or 1.

15. The peptide of Claim 1 wherein X includes the following structure X50:
-R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.

16. The peptide of Claim 1 wherein X includes the following structure X52:
-R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.

17. The peptide of Claim 1 wherein X includes the following structure X54:
-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic amino acid or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.

18. The peptide of Claim 1 wherein X includes the following structure X56:
-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline.

19. The peptide of Claim 1 wherein X includes the following structure X58:

-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R42-RR41-R43, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.

20. The peptide of Claim 1 wherein X includes the following structure X60:

R41-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or netural hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.

21. The peptide of Claim 1 wherein X has a structure selected from the group consisting of:
(a) R41-R42-R42-R41-R42-R42-R41;
(b) R41-R41-R42-R42-R41-R42-R42-R41;
(c) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(d) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and (e) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid.

22. A process for inhibiting the growth of a target cell, virus, or virally-infected cell in a host, comprising:
administering to a host a C-terminal substituted peptide or protein of the formula:
, wherein X is a biologically active amphiphilic peptide or protein, said peptide or protein being an ion channel-forming peptide or protein, and T is selected from the group consisting of:
(a) O-R, wherein R is a substituted or unsubstituted aliphatic, aromatic, or aralkyl group having from 1 to 10 carbon atoms;
(b) NH-NH2;
(c) NH-OH; and (d) , wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein group (i) is a hydroxy-substituted aliphatic, aromatic or aralkyl group having no more than 10 carbon atoms, and group (ii) is an amino-substituted aliphatic, aromatic, aralkyl, or alkylaromatic group, and at least one of R' and R" is group (i) or group (ii).
wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein group (i) is (CH2)n-OH; and group (ii) is (CH2)n-NH2, wherein n is from 1 to 10 and wherein at least one of R' and R" is group (i) or group (ii).

23. The process of Claim 22 wherein T is NH-CH2CH2-OH.

24. The process of Claim 22 wherein T is NH-CH2CH2-NH2.

25. The process of Claim 22 wherein X is a magainin peptide.

26. The process of Claim 22 wherein X is a PGLa peptide.

27. The process of Claim 22 wherein X is an XPF peptide.

28. The process of Claim 22 wherein X is a CPF peptide.

29. The process of Claim 22 wherein X is a cecropin.

30. The process of Claim 22 wherein X is a sarcotoxin.

31. The process of Claim 22 wherein X includes one of the following basic structures X31 through X37, wherein:
X31 is -[R31-R32-R32-R33-R31-R32-R32]n-;
X32 is -[R32-R32-R33-R31-R32-R32-R31]n-' X33 is -[R32-R33-R31-R32-R32-R31-R32]n-;
X34 is -[R33-R31-R32-R32-R31-R32-R32]n-;
X35 is -[R31-R32-R32-R31-R32-R32-R33]n-;
X36 is -[R32-R32-R31-R32-R32-R33-R31]n-' and X37 is -[R32-R31-R32-R32-R33-R31-R32]n, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and n is from 2 to 5.

32. The process of Claim 22 wherein the X includes the following basic structure X40:
R31-R32-R32-R33-R34-R32-R32-R31-R32-R32-R32-R34-R32-R32, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid.

33. The process of Claim 32 wherein X includes the following structure:
Y40-X40, wherein X40 is as herienabove described in Claim 32, and Y40 is:
(i) R32-, or ii) R32-R32-; or (iii) R34-R32-R32-; or (iv) R33-R34-R32-R32; or (v) R32-R33-R34-R32-R32; or (vi) R32-R32-R33-R34-R32-R32; or (vii) R31-R32-R32-R33-R34-R32-R32.

34. The process of Claim 32 wherein X includes the following structure:
X40-Z40, wherein X40 is as hereinabove described in Claim 32, and Z40 is:
(i) R31-; or (ii) R31-R32-; or (iii) R31-R32-R32; or (iv) R31-R32-R32-R33; or (v) R31-R32-R32-R33-R34; or (vi) R31-R32-R32-R33-R34-R32; or (vii) R31-R32-R32-R33-R34-R32-R32.

35. The process of Claim 32 wherein the peptide includes the following structure:
(Y40)a-X40-(Z40)b, wherein Y40 and Z40 are as previously defined in Claims 33 and 34, a is 0 or 1, and b is 0 or 1.

36. The process of Claim 22 wherein X includes the following structure X50:
-R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.

37. The process of Claim 22 wherein X includes the following structure X52:
-R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.

38. The process of Claim 22 wherein X includes the following structure X54:
-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.

39. The process of Claim 22 wherein X includes the following structure X56:
-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline.

40. The process of Claim 22 wherein X includes the following structure X58:
-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R42-R41-R43, R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.

41. The process of Claim 22 wherein X includes the following structure X60:

-R41-R42-R42-R41-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.

42. The process of Claim 22 wherein X has a structure selected from the group consisting of:
(a) R41-R42-R42-R41-R42-R42-R41;
(b) R42-R41-R42-R42-R41-R42-R42-R41;
(c) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(d) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and (e) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.

43. The process of Claim 22 wherein the peptide is administered in an amount effective in inhibiting growth of a target cell, virus or virally-infected cell.