JPH0278631A - Antiviral agent - Google Patents
Antiviral agentInfo
- Publication number
- JPH0278631A JPH0278631A JP63228843A JP22884388A JPH0278631A JP H0278631 A JPH0278631 A JP H0278631A JP 63228843 A JP63228843 A JP 63228843A JP 22884388 A JP22884388 A JP 22884388A JP H0278631 A JPH0278631 A JP H0278631A
- Authority
- JP
- Japan
- Prior art keywords
- peptide
- gly
- amino acid
- arg
- asp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003443 antiviral agent Substances 0.000 title claims abstract description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 28
- 150000001413 amino acids Chemical group 0.000 claims abstract description 17
- 241000700605 Viruses Species 0.000 claims abstract description 16
- 235000001014 amino acid Nutrition 0.000 claims abstract description 9
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 7
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 7
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 6
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical group C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000018102 proteins Nutrition 0.000 claims abstract description 5
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 5
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 5
- 230000002378 acidificating effect Effects 0.000 claims abstract description 4
- 239000004471 Glycine Chemical group 0.000 claims abstract description 3
- 108010077895 Sarcosine Chemical group 0.000 claims abstract description 3
- 235000004279 alanine Nutrition 0.000 claims abstract description 3
- 229940043230 sarcosine Drugs 0.000 claims abstract description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 244000063299 Bacillus subtilis Species 0.000 abstract description 7
- 235000014469 Bacillus subtilis Nutrition 0.000 abstract description 7
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 abstract description 4
- 241000991587 Enterovirus C Species 0.000 abstract description 3
- 208000006454 hepatitis Diseases 0.000 abstract description 3
- 231100000283 hepatitis Toxicity 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 241000701161 unidentified adenovirus Species 0.000 abstract description 3
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 108010089975 arginyl-glycyl-aspartyl-serine Proteins 0.000 abstract 2
- NNRFRJQMBSBXGO-CIUDSAMLSA-N (3s)-3-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O NNRFRJQMBSBXGO-CIUDSAMLSA-N 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 5
- 239000011347 resin Substances 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- SEFVRKXJJPMVHQ-YUMQZZPRSA-N (2s)-2-[[2-[[(2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]butanedioic acid Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O SEFVRKXJJPMVHQ-YUMQZZPRSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- -1 Arg-Gly-Asp- 3er Chemical compound 0.000 description 3
- 241000322342 Bacillus phage M2 Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 3
- 102000023732 binding proteins Human genes 0.000 description 3
- 108091008324 binding proteins Proteins 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 108010019407 glycyl-arginyl-glycyl-aspartic acid Proteins 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 101710192606 Latent membrane protein 2 Proteins 0.000 description 2
- 101710109576 Terminal protein Proteins 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- MDNRBNZIOBQHHK-KWBADKCTSA-N (2s)-2-[[(2s)-2-[[2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-3-carboxypropanoyl]amino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCN=C(N)N MDNRBNZIOBQHHK-KWBADKCTSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- AUFHLLPVPSMEOG-YUMQZZPRSA-N Arg-Gly-Glu Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(O)=O AUFHLLPVPSMEOG-YUMQZZPRSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000701844 Bacillus virus phi29 Species 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010091818 arginyl-glycyl-aspartyl-valine Proteins 0.000 description 1
- 108010009111 arginyl-glycyl-glutamic acid Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- IWHCAJPPWOMXNW-LYKMMFCUSA-N peptide t Chemical compound C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H]([C@H](O)C)C(O)=O)CC1=CC=C(O)C=C1 IWHCAJPPWOMXNW-LYKMMFCUSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000007160 ty medium Substances 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は、末端にタンパク質を持つ核酸（ＤＮＡ又はＲ
ＮＡ）を有するウィルスの増殖に対し阻害作用を有する
生理活性ペプチドに関する。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to nucleic acids (DNA or R
The present invention relates to a physiologically active peptide that has an inhibitory effect on the proliferation of a virus having NA).
［従来の技術］
５′末端に結合タンパク質を持つ核酸を有するウィルス
として、枯草菌ファージ、アデノウィルス、ポリオウィ
ルス、肝炎ウィルス等が知られている。これらのウィル
スの殆どは、人に対して各種の感染症を引き起こすため
、種々の抗ウィルス剤の開発が行われている。[Prior Art] Bacillus subtilis phage, adenovirus, poliovirus, hepatitis virus, etc. are known as viruses having a nucleic acid with a binding protein at the 5' end. Since most of these viruses cause various infectious diseases in humans, various antiviral agents are being developed.
ところで、Ａｒｇ−Ｇｌｙ−Ａｓｐ、Ａｒｇ−Ｇｌｙ−
Ａｓｐ−５ｅｒ。By the way, Arg-Gly-Asp, Arg-Gly-
Asp-5er.
Ａｒｇ−Ｇ］、ｙ−Ａｓｐ−Ｖａｌ、 Ｇｌｙ−Ａｒｇ
−Ｇｌｙ−Ａｓｐ、 Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ａｓｐ
−５ｅｒ、 Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ｇｌｕ−３ｅｒ
、Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−３ｅｒ−Ｐｒｏ、
Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ｇｌｕ−５ｅｒ−Ｐｒｏ等
の簡単なアミノ酸配列からなるペプチドが、フィブロネ
クチンの接着阻害を起させ、癌細胞の転移抑制作用を有
することが知られている（例えば、 Ｈｕｍｐｈｒｉｅ
ｓ、Ｍ、Ｊ、ｅｔ ａｌ、、５ｃｉｅｎｃｅ、２３３．
ｐ４６７−４７０、Ｈｕｍｐｈｒｉｅｓ、Ｍ、Ｊ、ｅｔ
ａｌ、、Ｊ、Ｃｅ１ｌ Ｂｉｏｌ、、］０３、ｐ２６
３７−２６４７、ｌｌｕｍｐｈｒｉｅｓ、Ｍ、Ｊ、ｅｔ
ａｌ、、Ｊ、Ｃ１１ｎＩｎｖｅｓｔ、、８１．ｐ７８
２−７９０等参照）。しかし、上記のペプチドが、ウィ
ルスの増殖を抑制する作用を有することは知られていな
い。Arg-G], y-Asp-Val, Gly-Arg
-Gly-Asp, Gly-Arg-Gly-Asp
-5er, Gly-Arg-Gly-Glu-3er
, Gly-Arg-Gly-Asp-3er-Pro,
It is known that peptides consisting of simple amino acid sequences such as Gly-Arg-Gly-Glu-5er-Pro inhibit fibronectin adhesion and have the effect of suppressing metastasis of cancer cells (for example, Humphrie
S, M, J, et al., 5science, 233.
p467-470, Humphries, M, J, et
al,, J, Ce1l Biol,,]03, p26
37-2647, llumpries, M, J, et
al,,J,C11nInvest,,81. p78
2-790 etc.). However, it is not known that the above-mentioned peptides have the effect of suppressing the proliferation of viruses.
［発明が解決しようとする課題］
本発明は、かかる現状に鑑み、合成の容易な簡単なアミ
ノ酸配列のペプチドからなる新規な抗ウィルス剤を提供
することを特徴とする特許である。[Problems to be Solved by the Invention] In view of the current situation, the present invention is a patent characterized by providing a novel antiviral agent consisting of a peptide with a simple amino acid sequence that is easy to synthesize.
［課題を解決するための手段］
本発明者は、上述した５′末端に結合タンパク質を持つ
核酸、すなわち、ＤＮＡ或いはＲＮＡの結合タンパク質
中に、所定のアミノ酸配列を含むヘプチドをレセプトす
る部位が存在し、当該部位にペプチドがレセプトされる
ことにより、ＤＮＡの複製が阻害され、ウィルスの増殖
が抑制されることを見出した。本発明は、かかる知見に
基づきなされたものである。[Means for Solving the Problems] The present inventors have discovered that in the above-mentioned nucleic acid having a binding protein at its 5' end, that is, a binding protein of DNA or RNA, there is a site that accepts a heptide containing a predetermined amino acid sequence. However, they discovered that by receiving a peptide at this site, DNA replication is inhibited and virus proliferation is suppressed. The present invention has been made based on this knowledge.
すなわち、本発明は、末端にタンパク質を持つ核酸を有
するウィルスに対する抗ウィルス剤として、次式の
ＸニーＸ２−Ｘ。That is, the present invention uses the following formula as an antiviral agent against a virus having a nucleic acid with a protein at its end.
（Ｘ、は塩基性アミノ酸を、Ｘ２はアラニン、グリシン
又はサルコシンを、Ｘ、は酸性アミノ酸を表わす）のア
ミノ酸配列を含むペプチドからなるものである。(X represents a basic amino acid, X2 represents alanine, glycine or sarcosine, and X represents an acidic amino acid).
上記塩基性アミノ酸としては、ヒスチジン、リジン、ア
ルギニンを、また酸性アミノ酸は、アスパラギン酸、グ
ルタミン酸を挙げることが出来る。Examples of the basic amino acids include histidine, lysine, and arginine, and examples of the acidic amino acids include aspartic acid and glutamic acid.
本発明のペプチドは、上記アミノ酸配列をその一部に含
んでいるものであれば良く、上記アミノ酸配列の両端に
、さらに他のアミノ酸を結゛合させても良い。The peptide of the present invention may contain the above amino acid sequence as a part thereof, and other amino acids may be bonded to both ends of the above amino acid sequence.
本発明の、特に好ましいヘプチドを例示すると次の通り
である。Examples of particularly preferred heptides of the present invention are as follows.
Ａｒｇ−Ｇｌｙ−Ａｓｐ、 Ａｒｇ−Ｇｌｙ−Ａｓｐ−
３ｅｒ、 Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｖａｌ、Ｇｌｙ−
Ａｒｇ−Ｇｌｙ−Ａｓｐ、 Ｇｌｙ−Ａｒｇ−Ｇｌｙ−
Ａｓｐ−５ｅｒ、Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ｇｌｕ−５
ｅｒ、 Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ａｓｐ−５ｅｒ−Ｐ
ｒｏ、、Ｇｌｙ−Ａｒｇ−Ｇｌｙ−Ｇｌｕ−５ｅｒ−Ｐ
ｒｏ、 Ａｒｇ−Ｇｌｙ−Ｇｌｕ。Arg-Gly-Asp, Arg-Gly-Asp-
3er, Arg-Gly-Asp-Val, Gly-
Arg-Gly-Asp, Gly-Arg-Gly-
Asp-5er, Gly-Arg-Gly-Glu-5
er, Gly-Arg-Gly-Asp-5er-P
ro,,Gly-Arg-Gly-Glu-5er-P
ro, Arg-Gly-Glu.
Ａｒｇ−３ａｒ−Ａｓｐ。Arg-3ar-Asp.
これらのペプチドは、固相法、液相法等、通常用いられ
るペプチド合成手法により得ることができる。また、精
製にあたっては、ゲルが過、イオン交換ゲルクロマトグ
ラフィー、逆相高速液体クロマトグラフィー等のペプチ
ド精製に通常用いられる手法を用いることができる。These peptides can be obtained by commonly used peptide synthesis techniques such as solid phase methods and liquid phase methods. Further, for purification, techniques commonly used for peptide purification such as gel filtration, ion exchange gel chromatography, and reversed phase high performance liquid chromatography can be used.
尚、本発明のペプチドは、末端にタンパク質を持つ核酸
、すなわち、ＤＮＡ或いはＲＮＡを有するウィルスであ
れば、特に区別することなく増殖阻害作用を有する。こ
れは、末端タンパク質に存在する上記ペプチドのレセプ
ターがウィルス間で差がなく、また、この種のＤＮＡ又
はＲＮＡの複製が、先ず、一方の鎖だけが鋳型になり、
末端まで複製されたあと、次いで、もう一方の鎖の合成
が行われるプロティンプライミング−置換型複製機構で
あり、末端タンパク質に上記ペプチドがレセプトされる
ことにより、前記複製機構が鋤かなくなるためである。The peptide of the present invention has a growth-inhibiting effect regardless of whether it is a virus that has a nucleic acid with a protein at its end, that is, DNA or RNA. This is because the receptor for the above-mentioned peptide present in the terminal protein is the same among viruses, and when this type of DNA or RNA is replicated, only one strand serves as a template.
This is a protein priming-displacement replication mechanism in which the other chain is synthesized after being replicated to the end, and the replication mechanism is no longer plowed by the reception of the peptide by the terminal protein. .
尚、これらのウィルスとしては、枯草菌ファージφ２９
、枯草菌ファージＭ２、アデノウィルス。In addition, these viruses include Bacillus subtilis phage φ29
, Bacillus subtilis phage M2, adenovirus.
ポリオウィルス、肝炎ウィルス等を例示できる。Examples include poliovirus and hepatitis virus.
尚、上記ペプチドは、ウィルス１μｇに対して、０．０
１〜１０００ａ＋ｇ程度用いると良い。In addition, the above peptide has a concentration of 0.0 per 1 μg of virus.
It is good to use about 1 to 1000a+g.
次に、実施例を挙げて本発明を具体的に説明するが、本
発明はこの実施例により制限されるものではない。Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.
［実施例コ
（ペプチドｔ（−Ａｒｇ−Ｇｌｙ−Ａｓｐ−Ｏｎの合成
）ｔ−ブトキシカルボニル−し−アスパラギン酸−β−
シクロヘキシルエステル２ｇを水・メタノール（１：３
）２０ｍｌに溶解し、１０重量％濃度の炭酸セシウム水
溶液を加えてＰＨ７にした。これを減圧濃縮してメタノ
ールを除去した後、凍結乾燥して、２．４ｇのｔ−ブト
キシカルボニル−Ｌ−アスパラギン酸−β−シクロヘキ
シルエステル−α−セシウム塩の結晶を得た。[Example 2 (Synthesis of peptide t(-Arg-Gly-Asp-On) t-butoxycarbonyl-s-aspartic acid-β-
2g of cyclohexyl ester was added to water/methanol (1:3).
), and the pH was adjusted to 7 by adding a 10% by weight aqueous cesium carbonate solution. This was concentrated under reduced pressure to remove methanol, and then freeze-dried to obtain 2.4 g of crystals of t-butoxycarbonyl-L-aspartic acid-β-cyclohexyl ester-α-cesium salt.
次に、上記で得られたｔ−ブトキシカルボニル−し−ア
スパラギン酸−β−シクロヘキシルエステル−α−セシ
ウム塩の１．１２ｇをジメチルホルムアミド６ｏ耐に溶
解し、クロロメチル樹脂（ペプチド研究所層、ジビニル
ベンゼン１％含有、２ｏＯ〜４００メツシユ、クロル含
量０．６５＋ｓｅｑ／ｇ） １０ ｇを加え、５０℃、
２４時間反応した。Next, 1.12 g of the t-butoxycarbonyl-shi-aspartic acid-β-cyclohexyl ester-α-cesium salt obtained above was dissolved in dimethylformamide 6O resistant, and chloromethyl resin (peptide research layer, divinyl Add 10 g of benzene (1% benzene content, 2oO~400 mesh, chloro content 0.65+seq/g), and heat at 50°C.
It reacted for 24 hours.
反応後のアスパラギン酸含量は、０ 、２５ ｍｍｏｌ
／ｇ−樹脂であった。その後、グラスフィルター上で濾
過することにより、ジメチルホルムアミドを除き、ジメ
チルホルムアミド、９０％ジメチルホルムアミド−水、
ジメチルホルムアミド、エタノールの順で洗浄し、乾燥
した。Aspartic acid content after reaction is 0.25 mmol
/g-resin. Thereafter, dimethylformamide was removed by filtration on a glass filter, and dimethylformamide, 90% dimethylformamide-water,
It was washed with dimethylformamide and ethanol in that order and dried.
このようにして得られたｔ−ブトキシカルボニル−し−
アスパラギン酸−樹脂５ｇ（１，２５ｍｍｏｌ）を塩化
メチレン中、５０％濃度のトリフルオロ酢酸水溶液で処
理して、ｔ−ブトキシカルボニル基をはずし、ｔ−ブト
キシカルボニル−グリシン（ペプチド研究新製）３ 、
１２５ｍｍｏｌをジシクロへキシルカルボジイミドを用
いて結合させた。The thus obtained t-butoxycarbonyl-
5 g (1.25 mmol) of aspartic acid-resin was treated with a 50% concentration aqueous trifluoroacetic acid solution in methylene chloride to remove the t-butoxycarbonyl group, and t-butoxycarbonyl-glycine (manufactured by Peptide Research Shinsei) 3,
125 mmol was coupled using dicyclohexylcarbodiimide.
これを塩化メチレン中、５０％濃度のトリフルオロ酢酸
水溶液で処理して、ｔ−ブトキシカルボニル基をはずし
、ｔ−ブトキシカルボニル−Ｎｕ−パラトルエンスルホ
ニル−し−アルギニン（ペプチド研究新製）３ 、１２
５ｍｍｏｌをジシクロへキシルカルボジイミドを用いて
結合させた。This was treated with a 50% trifluoroacetic acid aqueous solution in methylene chloride to remove the t-butoxycarbonyl group, and the t-butoxycarbonyl-Nu-paratoluenesulfonyl-cyarginine (manufactured by Peptide Research Shinsei) 3,12
5 mmol was coupled using dicyclohexylcarbodiimide.
尚、以上の反応は、ベックマン社製のペプチドシンセサ
イザーモデル９９０Ｅを用いて行った。The above reaction was performed using a peptide synthesizer model 990E manufactured by Beckman.
上述した方法で得たペプチド樹脂全量を、アニソールの
存在下に、フッ化水素で、０℃、１時間反応させ、脱保
護及びクロロメチル樹脂の脱離を行い、１規定の酢酸に
溶解して乾燥凍結した後、逆相高速液体クロマトグラフ
ィーにより精製し、白色の粉末であるペプチドＨ−Ａｒ
ｇ−Ｇｌｙ−Ａｓｐ−ＯＢ １８９ ｍｇを得た。The entire amount of the peptide resin obtained by the above method was reacted with hydrogen fluoride in the presence of anisole at 0°C for 1 hour to deprotect and remove the chloromethyl resin, and then dissolve it in 1N acetic acid. After drying and freezing, the peptide H-Ar was purified by reverse-phase high-performance liquid chromatography to obtain peptide H-Ar, which is a white powder.
189 mg of g-Gly-Asp-OB was obtained.
（ファージＤＮＡの調製）
枯草菌（Ｂａｃｉｌｌｕｓ ５ｕｂｔｉｌｉｓ ２２２
）をトリプトン−酵母エキス培地（ＴＹ培地）で培養し
、対数増殖期にバクテリオファージＭ２を感染させ、３
７℃で、１．５時間保持して完全に溶菌させた。得られ
たファージＭ２を、ＣｓＣｌグラジェントによる遠心分
離で精製した。次いで、これをＳＳＣバッファー溶液に
懸濁し、１０”ＰＦυ（ｐｌａｑｕｅ ｆｏｒｍｉｎｇ
ｕｎｉｔｓ）／ｍｌになるまで希釈し、ラウロイルサ
ルコシンナトリウム（ＳｏｄｉｕｍＬａｕｒｏｙｌ ５
ａｒｃｏｓｉｎａｔｅ（ＳＬＳ））を２％になるように
加え、室温で５〜１０分放置した。これをＳＳＣ／＜ッ
ファー溶液で飽和させたフェノールを当量加え、室温で
１０分間振盪し、７０００ｒｐ麿で、５分間遠心分離し
、フェノールを除去した。これを再度ＳＳＣバッファー
飽和フェノールで抽出し、ＤＮＡ層を４℃で、ＳＳＣバ
ッファー溶液に対して透析した。この場合のＡ２６０／
Ａ２８０ｎｍは１．８〜２．０とした。(Preparation of phage DNA) Bacillus subtilis 222
) was cultured in tryptone-yeast extract medium (TY medium) and infected with bacteriophage M2 during the logarithmic growth phase.
The cells were kept at 7°C for 1.5 hours to completely lyse the bacteria. The resulting phage M2 was purified by centrifugation using a CsCl gradient. Next, this was suspended in SSC buffer solution, and 10"PFυ (plaque forming
units)/ml, and diluted with sodium lauroyl sarcosine (Sodium Lauroyl 5
arcosinate (SLS)) was added at a concentration of 2%, and the mixture was left at room temperature for 5 to 10 minutes. To this was added an equivalent amount of phenol saturated with SSC/< buffer solution, shaken at room temperature for 10 minutes, and centrifuged at 7000 rpm for 5 minutes to remove phenol. This was extracted again with SSC buffer-saturated phenol, and the DNA layer was dialyzed against the SSC buffer solution at 4°C. A260/ in this case
A280nm was set to 1.8 to 2.0.
尚、上記と同様の方法で、末端にペプチドを有しないＤ
ＮＡをもつファージである５Ｐ５０についても、ＤＮＡ
を調製し、これをコントロールとして用いた。In addition, using the same method as above, D
Regarding 5P50, which is a phage with NA, DNA
was prepared and used as a control.
（コンピテントセルの調製）
枯草菌（Ｂａｃｉｌｌｕｓ ５ｕｂｔｉｌｉｓ ２２２
）をＴＢＡＢ（Ｔｒｙ−ｐｔｏｓｅ Ｂｌｏｏｄ Ａｇ
ａｒ Ｂａ５ｅ）培地により、３０〜３５℃で一晩増殖
させ、これをＣＩ培地にＯＤ、、、で０．０８となるよ
うに植種した。これを３５〜３６℃で、４時間振盪培養
した。次に。(Preparation of competent cells) Bacillus subtilis 222
) to TBAB (Try-ptose Blood Ag
The cells were grown overnight at 30 to 35°C in ar Ba5e) medium, and then inoculated into CI medium at an OD of 0.08. This was cultured with shaking at 35-36°C for 4 hours. next.
これを遠心分離して、菌を集め、２倍容のＣ■培地に懸
濁し、３５〜３６℃で、１時間振盪培養し、コンピテン
トセル溶液を得た。This was centrifuged to collect the bacteria, suspended in 2 times the volume of C2 medium, and cultured with shaking at 35-36°C for 1 hour to obtain a competent cell solution.
（抗ウイルス作用試験）
前記のファージＤＮＡの調製に記載した方法で得たｊμ
ｇ／ｍｌ濃度のファージＤＮＡのＳＳＣバッファー溶液
１００μｍと上記で合成した３ｎａｇ／ｍｌ濃度のＡｒ
ｇ−Ｇｌｙ−Ａｓｐペプチド水溶液の所定量とを混合し
、３７℃で、１ｅ分間インキュベートし、Ｄ Ｎ Ａ
−Ａｒｇ−Ｇｌｙ−Ａｓｐインキュベート液を得た。(Antiviral activity test) jμ obtained by the method described in the preparation of phage DNA above.
100 μm of SSC buffer solution of phage DNA at a concentration of 3 nag/ml and Ar synthesized above at a concentration of 3 nag/ml.
g-Gly-Asp peptide aqueous solution and incubated at 37°C for 1 e min.
-Arg-Gly-Asp incubation solution was obtained.
次に、上記コンピテントセル溶液５００μ・ｌとこのＤ
Ｎ Ａ −Ａｒｇ−Ｇｌｙ−Ａｓｐインキュベート液
を混合し、３０℃で、３０分間インキュベー１〜した。Next, add 500 μl of the competent cell solution and this D
The NA-Arg-Gly-Asp incubation solution was mixed and incubated at 30°C for 30 minutes.
ＬＴＴプレートにトリプトン−酵母エキス培地を入れ、
これに枯草菌（Ｂａｃｉｌｌｕｓ ５ｕｂｔｉｌｉｓＳ
Ｒ２２）をまき、上記のインキュベート液をスプレッダ
−でブレーティングした。これを、３７℃で一晩培養し
た後、プラークの数を数え、コントロールに対するプラ
ークの割合としてトランスフェクション効率を求めた。Put tryptone-yeast extract medium in LTT plate,
In this, Bacillus subtilis (Bacillus 5ubtilisS)
R22) was sown, and the above incubation solution was brated with a spreader. After culturing this overnight at 37°C, the number of plaques was counted and the transfection efficiency was determined as the ratio of plaques to the control.
この結果を図に、Ａｒｇ−Ｇｌｙ−Ａｓｐの濃度との関
係で示した。The results are shown in the figure in relation to the concentration of Arg-Gly-Asp.
この結果から明らかなように、本発明のペプチドが抗ウ
ィルス作用を有することが分かる。As is clear from this result, it can be seen that the peptide of the present invention has an antiviral effect.
発明の効果
以上のように本発明は、合成が極めて容易なペプチドで
、新たな抗ウィルス剤として有効なものである。Effects of the Invention As described above, the present invention is a peptide that is extremely easy to synthesize and is effective as a new antiviral agent.
図面は、抗ウイルス作用試験の結果を示したもので、Ａ
ｒｇ−Ｇｌｙ−Ａｓｐの濃度を変えた場合のプラークの
数の変化を表わしたものである。The figure shows the results of the antiviral effect test.
This figure shows the change in the number of plaques when the concentration of rg-Gly-Asp is changed.
Claims (1)
シン又はサルコシンを、Ｘ＿３は酸性アミノ酸を表わす
）のアミノ酸配列を含むペプチドからなる末端にタンパ
ク質を持つ核酸を有するウィルスに対する抗ウィルス剤
。(1) It has a nucleic acid with a protein at the end consisting of a peptide containing the amino acid sequence of the following formula X_1-X_2-X_3 (X_1 represents a basic amino acid, X_2 represents alanine, glycine or sarcosine, and X_3 represents an acidic amino acid) Antiviral agent against viruses.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63228843A JP2646013B2 (en) | 1988-09-14 | 1988-09-14 | Antiviral agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63228843A JP2646013B2 (en) | 1988-09-14 | 1988-09-14 | Antiviral agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0278631A true JPH0278631A (en) | 1990-03-19 |
| JP2646013B2 JP2646013B2 (en) | 1997-08-25 |
Family
ID=16882735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63228843A Expired - Fee Related JP2646013B2 (en) | 1988-09-14 | 1988-09-14 | Antiviral agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2646013B2 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0378432A2 (en) * | 1989-01-13 | 1990-07-18 | Richter Gedeon Vegyeszeti Gyar R.T. | Novel peptides, their use to inhibit the maturation of t-lymphocytes and the activity of macrophages, and processes for their preparation |
| US5686566A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5780595A (en) * | 1989-06-16 | 1998-07-14 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US6057155A (en) * | 1995-11-28 | 2000-05-02 | Genvec, Inc. | Targeting adenovirus with use of constrained peptide motifs |
| US6127525A (en) * | 1995-02-21 | 2000-10-03 | Cornell Research Foundation, Inc. | Chimeric adenoviral coat protein and methods of using same |
| US6455314B1 (en) | 1998-09-11 | 2002-09-24 | Genvec, Inc. | Alternatively targeted adenovirus |
| US6951755B2 (en) | 1994-09-08 | 2005-10-04 | Genvec, Inc. | Vectors and methods for gene transfer |
-
1988
- 1988-09-14 JP JP63228843A patent/JP2646013B2/en not_active Expired - Fee Related
Cited By (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0378432A2 (en) * | 1989-01-13 | 1990-07-18 | Richter Gedeon Vegyeszeti Gyar R.T. | Novel peptides, their use to inhibit the maturation of t-lymphocytes and the activity of macrophages, and processes for their preparation |
| US5795867A (en) * | 1989-06-16 | 1998-08-18 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5686569A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5795868A (en) * | 1989-06-16 | 1998-08-18 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5686567A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5807825A (en) * | 1989-06-16 | 1998-09-15 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5686571A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5756451A (en) * | 1989-06-16 | 1998-05-26 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5807828A (en) * | 1989-06-16 | 1998-09-15 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5770564A (en) * | 1989-06-16 | 1998-06-23 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5780595A (en) * | 1989-06-16 | 1998-07-14 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5786333A (en) * | 1989-06-16 | 1998-07-28 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5686566A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5686568A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregration inhibitors |
| US5686570A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5759999A (en) * | 1989-06-16 | 1998-06-02 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5843897A (en) * | 1989-06-16 | 1998-12-01 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5851839A (en) * | 1989-06-16 | 1998-12-22 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US5968902A (en) * | 1989-06-16 | 1999-10-19 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
| US6951755B2 (en) | 1994-09-08 | 2005-10-04 | Genvec, Inc. | Vectors and methods for gene transfer |
| US6127525A (en) * | 1995-02-21 | 2000-10-03 | Cornell Research Foundation, Inc. | Chimeric adenoviral coat protein and methods of using same |
| US6153435A (en) * | 1995-02-21 | 2000-11-28 | Cornell Research Foundation, Inc. | Nucleic acid that encodes a chimeric adenoviral coat protein |
| US6057155A (en) * | 1995-11-28 | 2000-05-02 | Genvec, Inc. | Targeting adenovirus with use of constrained peptide motifs |
| US6329190B1 (en) | 1995-11-28 | 2001-12-11 | Genvec, Inc. | Targetting adenovirus with use of constrained peptide motifs |
| US6649407B2 (en) | 1995-11-28 | 2003-11-18 | Genvec, Inc. | Targeting adenovirus with use of constrained peptide motifs |
| US6455314B1 (en) | 1998-09-11 | 2002-09-24 | Genvec, Inc. | Alternatively targeted adenovirus |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2646013B2 (en) | 1997-08-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP3266311B2 (en) | Novel polypeptide and anti-HIV agent using the same | |
| JPH08504837A (en) | Novel polypeptide and anti-HIV agent prepared therefrom | |
| JPS6222799A (en) | Novel polypeptide having blood anticoagulant action | |
| CA2023779A1 (en) | Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders | |
| JPH04503073A (en) | anaphylatoxin receptor ligand | |
| JPH0278631A (en) | Antiviral agent | |
| US4093610A (en) | Process for producing triglycyl-lysine vasopressin and intermediates therefor | |
| PT99940A (en) | PROCESS FOR THE PREPARATION OF HEXA- AND HEPTAPEPTIDIC LIGANDS OF ANAFILATOXINE RECEPTOR AND PHARMACEUTICAL COMPOSITIONS | |
| CA2421183C (en) | Novel polypeptide and anti-hiv agent containing the same | |
| JPH07324097A (en) | Interleukin 6 antagonist, peptides or pharmaceutically permissible salts thereof | |
| JPH06504050A (en) | Modified hexa- and hepta-peptide anaphylatoxin receptor ligands | |
| JPH02264796A (en) | Libonucleotide reductase inhibitor | |
| JPS61111695A (en) | B-type hepatitis virus, dna fragment, polypeptide and oligopeptide from b-type hepatitis virus component, production of recombined dna molecule, dna vector, eshericiacoli k12 variant and polypeptide, innoculant substance to b-type hepatitis virus disease, monocronal antibody ma18/7 and mouse hybrid cell gola18/7-1 and production of monocronal antibody ma 187 | |
| RU1836102C (en) | A way of obtaining a synthetic vaccine against barbs | |
| JPS60226898A (en) | Novel gonadoliberin derivative and manufacture | |
| JPH07289261A (en) | Gene of adhesive protein of mytilus edulis | |
| Sacchettini et al. | Purification, crystallization, and preliminary X-ray data for porcine fumarase. | |
| JPS6330318B2 (en) | ||
| JP4470152B2 (en) | Novel tripeptide and method for producing the same | |
| RU2106358C1 (en) | Polypeptide or its pharmaceutically acceptable salt (variants); method to suppress the action of amino acid neuromediators | |
| Isobe et al. | Characterization of the morphogenesis-dependent cleavage region of the major capsid protein (P23) of bacteriophage T4; sequence of an amber fragment of P23 | |
| US4389342A (en) | Synthetic hormone-like peptides and method for their synthesis | |
| JP3009718B2 (en) | New peptides, their production methods and applications | |
| JP2793216B2 (en) | Sorbin and derived peptides to enhance mucosal absorption | |
| JPS5892642A (en) | Novel peptides and manufacture |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313111 |
|
| R371 | Transfer withdrawn |
Free format text: JAPANESE INTERMEDIATE CODE: R371 |
|
| S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313111 |
|
| R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
| LAPS | Cancellation because of no payment of annual fees |