US20030229202A1 - Membrane penetrating peptides and uses thereof - Google Patents
Membrane penetrating peptides and uses thereof Download PDFInfo
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- US20030229202A1 US20030229202A1 US09/933,780 US93378001A US2003229202A1 US 20030229202 A1 US20030229202 A1 US 20030229202A1 US 93378001 A US93378001 A US 93378001A US 2003229202 A1 US2003229202 A1 US 2003229202A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
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- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/09—Fusion polypeptide containing a localisation/targetting motif containing a nuclear localisation signal
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
- C07K2319/43—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a FLAG-tag
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/50—Fusion polypeptide containing protease site
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/60—Fusion polypeptide containing spectroscopic/fluorescent detection, e.g. green fluorescent protein [GFP]
Definitions
- the invention relates to membrane penetrating peptides useful as in vitro, ex vivo and in vivo delivery devices for intracellular delivery of a compound of interest to cells in vitro, ex vivo and in vivo, compositions comprising the same and methods of using the same.
- the invention also includes identification of additional membrane penetrating peptides useful as delivery devices for intracellular delivery of a compound of interest to cells in vitro, ex vivo and in vivo.
- Fusion proteins containing the targeting sequence and another, otherwise non-targeted protein are localized in the selected cellular organelle depending on the targeting sequence selected.
- Ferullo, J. M. and Paget, E. FR 279695 disclose selective compartmentalization of an hydroxyphenylpyruvate dioxygenase (HPPD) fused to a signal sequence directing the enzyme to a cellular compartment other than the cytosol, e.g., a vacuole.
- HPPD hydroxyphenylpyruvate dioxygenase
- WO 0147950 Wehrle-Haller, Bernhard M.; Inhof, Beat A
- the signal is a mono-leucine dependent basolateral sorting signal consisting of the amino acid sequence X1h2X3h4Lp5p6, wherein: X1 represents a polar amino acid residue or alanine, h2 represents any hydrophobic amino acid residue, X3 represents any amino acid residue, h4 represents any hydrophobic amino acid residue, except leucine and isoleucine, L represents a leucine residue, p5 represents any polar amino acid residue, and p6 represents any polar amino acid.
- Richardson, A. E., et al., Plant J. (2001), 25(6), 641-649 describe manipulation of the enzyme aspergillus phytase to include the signal peptide sequence from the carrot extensin gene.
- WO 0132894 disclose use of the signal anchor domain sequences of type II cell surface proteins to anchor recombinant proteins into surface of transfected cells.
- a characteristic feature of type II cell surface proteins is that they are held within the cellular membrane by a single hydrophobic transmembrane domain and are oriented with their C-terminus outside the cell.
- MPPs membrane penetrating peptides
- TAT protein transduction domain
- VP22 protein transduction domain
- the present invention is directed to the discovery that polypeptides derived from mammalian or yeast proteins nuclear localization sequences (NLSs) or overlapping with NLS's are capable of acting as MPPs, and identification of a specific polypeptide sequences capable of penetrating cellular membranes, even when conjugated to large proteins, such as biologically active proteins, or other organic compounds.
- NLSs nuclear localization sequences
- Nuclear transport is essential to a number of biological processes including gene expression and cell division, as well as to viral replication, tumorigenesis and tumor cell proliferation.
- the mechanism of nuclear transport has only recently been characterized in detail and has been shown to involve a number of discrete steps.
- Proteins that are destined to be transported into the nucleus contain within their amino acid sequence a short stretch of amino acids termed a nuclear localization sequence (“NLS”). These sequences may occur anywhere within the amino acid sequence and are typically four to about eight amino acids. These sequences are generally basic (i.e., positively charged) in nature, however, there has been no consensus sequence identified. Thus, there is a wide variety of these sequences that appear to be specific for particular proteins.
- these NLSs may be either masked or unmasked by accessory proteins or by conformational changes within the NLS-containing protein.
- An NLS may be masked because it is buried in the core of the protein and not exposed on the surface of the protein.
- Unmasking of NLSs, and nuclear translocation of cytoplasmic proteins may be triggered by phosphorylation, dephosphorylation, proteolytic digestion, subunit association or dissociation of an inhibitory subunit, or the like. Accordingly, the masking and unmasking of NLSs provides a mechanism by which the transport of these cytoplasmic proteins into the nucleus may be regulated.
- the transcription factor NF-AT contains nuclear localization sequences which allow NF-AT to translocate to the nucleus in the presence of intracellular calcium, but which are shielded by forming intramolecular associations with other domains in the NF-AT polypeptide in the absence of calcium.
- CLS cytoplasmic localization sequences
- nuclear export sequences which ensure the protein remains predominantly in the cytoplasm.
- CCS cytoplasmic localization sequences
- hRPF1/Nedd4 a component of the ubiquitin-proteasome pathway responsible for substrate recognition and specificity, is capable of entering the nucleus, but the presence of a functional Rev-like nuclear export sequence in hRPF1/Nedd4 ensures a predominant cytoplasmic localization.
- the cytoplasmic domains of many membrane proteins contain sorting signals that mediate their endocytosis from the plasma membrane.
- TGN trans-Golgi network
- the mammalian endopeptidase, furin is predominantly localized to the trans-Golgi network (TGN) at steady state.
- the localization of furin to this compartment seems to be the result of a dynamic process in which the protein undergoes cycling between the TGN and the plasma membrane.
- TGN localization and internalization from the plasma membrane are mediated by targeting information contained within the cytoplasmic domain of furin.
- Voorhees, P., et al., EMBO J. (1995), 14(20), 4961-75 report that there are at least two cytoplasmic determinants that contribute to the steady-state localization and trafficking of furin.
- the first determinant corresponds to a canonical tyrosine-based motif, YKGL (residues 758-761), that functions mainly as an internalization signal.
- the second determinant consists of a strongly hydrophilic sequence (residues 766-783) that contains a large cluster of acidic residues (E and D) and is devoid of any tyrosine-based or di-leucine-based motifs. This second determinant is capable of conferring localization to the TGN as well as mediating internalization from the plasma membrane.
- the trans-Golgi network plays a central role in protein sorting/targeting and the sequence SXYQRL can by itself confer significant TGN localization.
- TGN trans-Golgi network
- Wong, S. H., and Hong, W. J. Biol. Chem. (1993), 268(30), 22853-62 report detailed mutagenesis of the 32-residue sequence of TGN38, an integral membrane protein confined mainly to the TGN, and determined that the Ser, Tyr, and Leu residues at positions 23, 25, and 28, respectively, are essential for TGN localization.
- the cytoplasmic 32-residue sequence of TGN38 was fused to the ecto- and transmembrane domains of glycophorin A (a surface protein), the resulting chimeric protein was localized to the TGN.
- NF- ⁇ B/I ⁇ B ⁇ complexes shuttle between the cytoplasm and nucleus by a nuclear localization signal-dependent nuclear import and a CRM1-dependent nuclear export and that the dominant nuclear export over nuclear import contributes to the largely cytoplasmic localization of the inactive complexes to achieve efficient NF- ⁇ B activation by extracellular signals.
- Nuclear import of classical nuclear localization sequence-containing proteins involves the assembly of an import complex at the cytoplasmic face of the nuclear pore complex (NPC) followed by movement of this complex through the NPC and release of the import substrate into the nuclear interior.
- NPC nuclear pore complex
- two other soluble factors are thought to be absolutely required to mediate the nuclear import of a protein containing a classical or basic NLS into the nucleus. The first is karyopherin/importin ⁇ (Kap ⁇ ), which binds a classical NLS and then forms a complex with karyopherin/importin ⁇ 1 (Kap ⁇ 1).
- Kap ⁇ karyopherin/importin ⁇
- Kap ⁇ 1 interacts with nuclear pore complex (NPC) proteins and appears to mediate movement of the import complex through the NPC via these interactions.
- NPC nuclear pore complex
- Another protein, p10/NTF2 has also been implicated in nuclear import, but its function may only be to take Ran into the nucleus, where it is subsequently needed to disassemble an incoming import complex.
- Kap ⁇ homologues in yeast (SRP1 or Kap60), vertebrate cells contain a number of proteins that can bind a classical NLS and share sequence homology (see Ref. Nachury, M. V., Ryder, U. W., Lamond, A. I., and Weis, K. (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 582-587, and references therein). These proteins have been given a variety of names but can be grouped into three major families.
- the Kap ⁇ 1 family contains the human protein NPI-1/importin ⁇ 1/karyopherin ⁇ 1/Rch2/hSRP1 and a second related protein importin ⁇ 6, in addition to the mouse S2 protein.
- the second family, Kap ⁇ 2 contains human Rch1/hSRP1/importin ⁇ 2/karyopherin ⁇ 2 and the mouse protein pendulin/PTAC 58. Görlich, D., Prehn, S., Laskey, R. A., and Hartmann, E. (1994) Cell 79, 767-778; Cuomo, C. A., Kirch, S. A., Gyuris, J., Brent, R., and Oettinger, M. A. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6156-6160; Kussel, P., and Frasch, M. (1995) Mol. Gen. Genet.
- each of these classes share about 50% homology with each other and to the yeast SRP1, and each of these mammalian proteins has been shown to be capable of mediating the import of one or more classical NLS-containing proteins.
- Stat-1 import is mediated by Kap ⁇ 1/NPI-1 but not Kap ⁇ 2/Rch1, but activated Stat-1 appears to bind to a COOH-terminal region of Kap ⁇ 1 distinct from the NLS binding Armadillo repeats.
- the binding differences of the different Kap ⁇ s to RCC1 observed appear to be due solely to the NLS on RCC1 and therefore probably due to the NLS binding region of Kap ⁇ 3.
- U.S. Pat. No. 6,191,269 teaches the existence of a nuclear localization sequence contained within the cDNA sequence of the N-terminal IL-1 alpha propiece, T76-NGKVLKKRRL, which had characteristics of a nuclear localization sequence (NLS) and could mediate nuclear localization of the propiece (Stevenson et al. (1997) Proc. Natl. Acad. Sci. USA 94:508-13).
- Introduction of the cDNA encoding the N-terminal IL-.alpha. propiece into cultured mesangial cells resulted in nuclear accumulation (Stevenson et al. id).
- U.S. Pat. No. 5,877,282 teaches that the antennapedia homeodomain signal sequence peptide is the amino acid sequence RQIKIWFQNRRMKWKK; the fibroblast growth factor signal sequence peptide is AAVALLPAVLLALLA; the HIV Tat signal sequence peptide is the amino acid sequence CFITKALGISYGRKKRRQRRRPPQGSQTH.
- Schwartze S. R., et al., Science 285:1569-1572 (1999) report delivery of an ip injected reporter protein, 116 kD beta-galactosidase, as a TAT fusion protein into tissues and across the blood-brain barrier.
- Schwartze used an 11 amino acid protein transduction domain (PTD) derived from HIV tat protein with an N-terminal fluorescein isothiocyanate (FITC)-Gly-Gly-Gly-Gly motif.
- FITC fluorescein isothiocyanate
- the authors report that earlier attempts to transduce beta-Gal chemically cross-linked to the TAT PTD resulted in sporadic and weak beta-Gal activity in a limited number of tissues. They speculate that the improved transduction was due to the in-frame fusion and purification strategy used.
- Nuclear localization of IFN ⁇ is mediated by a polybasic NLS in its C terminus, which is required for the full expression of biological activity of IFN ⁇ , both extracellularly and intracellularly.
- This NLS is thought to play an integral intracellular role in the nuclear translocation of the transcription factor STAT1 ⁇ activated by IFN ⁇ because treatment of IFN ⁇ with antibodies to the C-terminal region (95-133) containing the NLS blocked the induction of STAT1 ⁇ nuclear translocation, but these antibodies had no effect on nuclear translocation of STAT1 ⁇ in IFN ⁇ treated cells.
- the peptide representing amino acids 95-132 of IFN- ⁇ (IFN- ⁇ (95-132)), containing the polybasic sequence 126 RKRKRSR 132 , was capable of specifying nuclear uptake of the autofluorescent protein, APC, in an energy-dependent fashion that required both ATP and GTP. Nuclear import was abolished when the above polybasic sequence was deleted. Subramaniam, P., et al., 1999 J Biol Chem 274(1) 403-407.
- a peptide containing the prototypical polybasic NLS sequence of the SV40 large T-antigen was also able to inhibit the nuclear import mediated by IFN- ⁇ (95-132), suggesting that the NLS in IFN- ⁇ may function through the components of the Ran/importin pathway utilized by the SV40 T-NLS.
- Intact IFN- ⁇ when coupled to APC, was also able to mediate its nuclear import, and this nuclear import was blocked by the peptide IFN- ⁇ (95-132) and the SV40 T-NLS peptide, suggesting that intact IFN- ⁇ was also transported into the nucleus through the Ran/importin pathway.
- Nuclear proteins are imported into the nucleus through aqueous channels that span the nuclear envelope called nuclear pore complexes (NPCs). Although ions and molecules less than ⁇ 20-40 Da can diffuse passively through the nuclear pore complexes, larger proteins are transported by saturable pathways that are energy- and signal-dependent.
- the signals that specify nuclear protein import (NLSs)1 are commonly short stretches of amino acids rich in basic amino acid residues, although other classes of NLSs have been described recently.
- the initial step in the import of proteins containing basic amino acid-type NLSs occurs in the cytosol, where the NLS-containing proteins are bound to a receptor (variously called the NLS receptor, importin ⁇ , and karyopherin (13).
- the substrate-receptor complex then associates with the cytoplasmic face of the nuclear pore complexes, and with the participation of other cytosolic factors, is transported through a gated channel in the nuclear pore complexes to the nuclear interior.
- the in vivo events of NLS-mediated nuclear import can be duplicated in an in vitro system using digitonin-permeabilized cells supplemented with cytosolic extracts and ATP (14). Transport in this in vitro assay is blocked by the same inhibitors that block in vivo import, is rapid, and is easily quantified.
- FGF-1 fibroblast growth factor-1
- FGF-1 the precursor for acidic FGF
- FGF-1 contains an NTS
- nuclear translocation requires an exogenous and not an endogenous pathway.
- the NTS of FGF-1, NYKKPKL is able to direct the expression of the bacterial ⁇ -galactosidase ( ⁇ gal) gene to the nucleus of transfected NIH 3T3 cells, but this NTS is unable to target either FGF-1 itself of a FGF-1- ⁇ gal fusion protein into the nucleus, suggesting that FGF-1 may contain an additional sequence which prevents endogenously expressed FGF-1 from being translocated into the nucleus.
- Interferon- ⁇ a protein that uses the Jak-Stat pathway for signal transduction, translocates rapidly to the nucleus in cells treated extracellularly with the cytokine.
- An NLS has been identified and characterized in the C-terminus of human and murine IFN- ⁇ .
- Larkin, J., et al., J. Interferon Cytokine Res. (2001), 21(6), 341-348 report that human IFN- ⁇ (HuIFN- ⁇ ) contains a second NLS at an upstream site.
- the primary sequence, analogous with the NLS sequence identified in murine IFN- ⁇ , representing amino acids 122-132 of HuIFN- ⁇ was capable of mediating the nuclear import of the autofluorescent protein allophycocyanin (APC) in an energy-dependent manner.
- the second sequence, representing amino acids 78-92 of HuIFN- ⁇ was also capable of mediating the nuclear import of APC in an energy-dependent manner but to a greatly reduced extent.
- the nuclear import of both sequences conjugated to APC was strongly blocked by competition with unconjugated HuIFN- ⁇ (122-132).
- HuIFN- ⁇ (78-92) effectively blocked the import of APC-conjugated HuIFN- ⁇ (78-92) but, at the same concentration, was not capable of inhibiting the nuclear import of APC-conjugated HuIFN- ⁇ (122-132), suggesting that HuIFN- ⁇ (78-92) was a less efficient NLS than HuIFN- ⁇ (122-132). This is consistent with >90% loss of antiviral activity of HuIFN- ⁇ lacking the downstream NLS in 122-132.
- Cokel et al found an overlap between the NLS and DNA-binding region for 90% of the proteins for which both the NLS and DNA-binding regions were known, but only 56 of the 214 NLS motifs overlapped with DNA-binding regions. These 56 NLSs enabled a de novo prediction of partial DNA-binding regions for approximately 800 proteins in human, fly, worm and yeast.
- NLS signal peptide can induce structural changes of DNA.
- the plant enzyme, glutaminyl-tRNA synthetase (GlnRS) from Lupinus luteus contains an NLS at the N-terminal, a lysine rich polypeptide, KPKKKKEK. Krzyzaniak, A., et al., Mol. Biol. Rep. (2000), 27(1), 51-54.
- Two synthetic peptides (20 and 8 amino acids long), derived from the NLS sequence of lupin GlnRS interact with DNA.
- the shorter 8 amino acid peptide caused the DNA to change its conformation from the B to the Z form.
- the NLS in the N-terminal region of Smad 3 protein the major Smad protein involved in TGF- ⁇ signal transduction, has a basic motif Lys 40 - Lys-Leu-Lys-Lys 44 , which is conserved among all the pathway-specific Smad proteins, and is required for Smad 3 nuclear import in response to ligand.
- Smad proteins are intracellular mediators of transforming growth factor ⁇ (TGF- ⁇ ) and related cytokines.
- TGF- ⁇ transforming growth factor ⁇
- Xiao, Z., et al., J. Biol. Chem. (2000), 275(31), 23425-23428 identified the role the NLS plays in nuclear localization.
- Smad 3 MH1 domain displays significant specific binding to importin ⁇ , which is diminished or eliminated by mutations in the NLS.
- Full-size Smad 3 exhibits weak but specific binding to importin ⁇ , which is enhanced after phosphorylation by the type I TGF- ⁇ receptor.
- no interaction was observed between importin ⁇ and Smad 3 or its MH1 domain, indicating that nuclear translocation of Smad proteins may occur through direct binding to importin ⁇ .
- the lipid bilayer of cell membranes serves as a selective barrier for the passage of charged molecules, with the internalization of hydrophilic macromolecules being achieved through classical transport pathways (Hawiger, J., Curr Opin Chem Biol. 3, 89-94 (1999), Schwartze, S. R., et al., Trends in Cell Biology 10, 290-295 (2000)).
- These classical mechanisms of internalization involve receptor-mediated endocytosis or transporter dependent uptake (Cleves, A. E., Current Biology 7, R318-R320 (1997)).
- an increasing number of molecules have been discovered that lack classical import and/or export signals (Cleves, A. E., Current Biology 7, R318-R320 (1997)).
- Antp protein has not been shown to traverse biological membranes; however, a 16 amino acid synthetic peptide derived from within its coding region does possess potent membrane penetrating abilities (Derossi, D., et al, Trends Cell Biol., 8, 84-87 (1998)).
- the accepted view of atypical transport used by these molecules has been termed “transduction” (Schwarze, S.
- transducing peptides possess many different characteristics such as amino acid sequence, length of the sequence, cellular localization, and potency of membrane penetration. Thus, though each transducing sequence can penetrate cells and tissues, it has not been established whether they use the identical atypical transport mechanisms.
- U.S. Pat. No. 6,022,950 teaches the use of a hybrid molecule of a portion of the binding domain of a cell-binding polypeptide ligand effective to cause said hybrid protein to bind to a cell of an animal, a translocation domain of naturally occurring protein which translocates said third part across the cytoplasmic membrane into the cytosol of the cell; and a chemical entity to be introduced into the cell.
- the patent teaches translocation domains of toxins.
- Naturally-occurring proteins which are known to have a translocation domain include diphtheria toxin and Pseudomonas exotoxin A, and may include other toxins and non-toxin molecules, as well.
- the translocation domains of diphtheria toxin and Pseudomonas exotoxin A are well characterized (see, e.g., Hoch et al., Proc. Natl. Acad. Sci. USA 82:1692-1696, 1985; Colombatti et al., J. Biol. Chem. 261:3030-3035, 1986; and Deleers et al., FEBS 160:82-86, 1983), and the existence and location of such a domain in other molecules may be determined by methods such as those employed by Hwang et al., Cell 48:129-136, 1987; and Gray et al., Proc. Natl. Acad. Sci. USA 81:2645-2649, 1984.
- the present invention is directed to polypeptides derived from mammalian and yeast proteins useful as a carrier for in vitro, ex vivo and in vivo delivery a compound of interest.
- the invention also provides compositions containing the same, and methods of delivering a compound of interest in vitro, ex vivo and in vivo.
- FIG. 1.(A) Schematic diagram of hPER1 fusion constructs showing the locations of the PAS, cytoplasmic localization, and nuclear localization sequence (NLS, but indicated as nuclear localization domain (NLD) in Figure). The name and the position of the fusion constructs are listed on the left. The number indicates the first and last amino acid residues in the hPER1 protein. The principal sites of accumulation of each fusion protein are summarized on the right, (n) nuclear, (no) nucleoli, (c) cytoplasmic, (diff) diffuse. All constructs were N-terminally tagged with EYFP. The alignment human and mouse PER1-NLS is shown at the bottom.
- FIG. 1.(B) Cellular localization of hPER1 fusion proteins as described in FIG. 1A, above, in living cells. CHO cells were transient transfected with the fusion constructs indicated on the top of each panel and the subcellular localization of EYFP reporters (green) was directly visualized using fluorescent microscopy 10 h post-transfection. EYFP vector alone is used as control (see 5. EYFP-VECTOR)
- FIG. 3 Alanine scanning of hPER1-PDTs. Biotinylated hPER1-NPDs were synthesized with a single amino acid residue substitution at the indicated position with an alanine and assayed for membrane penetration in CHO cells. Cells were incubated for 10 minutes at 37 C. at a peptide concentration of 10 ⁇ M followed by washing, fixation, permeablization, and then detected with labeled Streptavidin Alexa-594 (red, 2 ⁇ g/ml) for 15 minutes at the RT. Control peptide was from hPER1 N-terminal amino acids residues 486-500.
- FIG. 4 Activation of serotonin 5HT2A receptor with hPER1-MPP fusion peptide.
- A hPER1-MPP and TAT-PTD peptides were synthesized alone or in fusion with either the first intracellular loop I1 (SLEKKLQNATN), or the C-terminal Transmembrane 7 domain, TM7 (KTYRSAFSRYIQYKENKKPLQLI) derived from the 5HT2A receptor, genebank accession numbr, M86841). Receptor activities was assayed using standard FLIPR analysis and measuring endogenous and exogenous Ca +2 levels.
- T T (TAT-PTD), P (hPER1-MPP), I1 (intracellular loop 1), T-I1 (TAT-PTD-I1), P-I1 (hPER1-MPP-I1), TM7 (C-terminal domain), TTM7 (TAT-PTD-TM7), PTM7 (hPER1-MPP-TM7), and S (Serotonin).
- FIG. 4(B) Dose response of PTM7 (closed circles) and TTM7 (closed diamonds) peptides. Serotonin (control, open triangle) was used at the maximum receptor stimulatory concentration of 10 ⁇ M.
- FIG. 5 Identification of additional PTDs.
- Putative PTD sequences were searched using a combined bioinformatics method that included SwissPro, PRF, PIR-Protein info Resource, PDB with peptides sequences translated from the annotated protein coding region in GenBank with “transcription factor” as the key word. We initially searched for all known or putative NLS's.
- FIG. 6 hPER-PTD cargo's ⁇ -Galactosidase into cells: At least one feature of HIV TAT transducing peptide is its ability to cargo proteins into cells and tissues. We therefore sought to determine if hPER1 transducing peptide could cargo beta galactosidase into cells. To perform this experiment, we followed a protocol by Frankel et al. 1989 (19):7397-401, whereby, we chemically linked hPER1-PTD or hPER-PTD R7A to full length ⁇ -galactosidase and assayed for the ability of these conjugates and beta-galactosidase protein alone to transduce into CHO cells. As shown in the FIG.
- the present invention is based on discovery that human Period1 (hPER1) protein contains an NLS which has now also been identified as an MPP and is useful as a delivery device for intracellular delivery of a compound of interest.
- hPER1 is involved in regulation of the circadian rhythm and the capacity of hPER1 to translocate to adjacent cells may be critical to its overall biological function of regulating circadian rhythm.
- the NLS identified within hPER1 does not fit within previously identified NLS sequences, and its identification has resulted in identification of an algorithm for searching for other NLS sequences which may also function as MPPs.
- Period 1 is a nuclear protein involved with transcriptional regulation. It is an essential component in the “gears” of the biological clock (Brown, S. A., and Schibler, U., Current Opinion in Genetics & Development 9, 588-594 (1999), Dunlap, J. C., Cell 96, 271-290 (1999)), and studies in mice have shown that nuclear entry of PER1 is essential for the down regulation of CLOCK/BMAL transcriptional complexes (Gekakis N, et al., Science 280, 1564-1569. (1998), Yagita, K., et al., Genes Dev 14,1353-1363 (2000), Lowrey, P.
- PER1 is a central component in the circadian clock, and its nuclear entry plays an important role in the regulation of daily oscillations (Jin, X., et al., Cell 96, 57-68 (1999), Sangoram, A. M., et al., Neuron 21, 1101-13 (1998 )).
- deletion and fusion protein analysis we identified a NLS that is necessary and sufficient for hPER1 nuclear localization. This functional analysis was necessary because the NLS of hPER1 does not conform to classical nuclear localizing consensus motifs; and therefore, was not identified using standard NLS search procedures.
- hPER1-NLS is located between amino acids (830-845) of hPER1, is embedded within a string of 13 amino acids rich in arginine, histidine, and lysine (see Table 1) that is not found in other PERs or other nuclear proteins in available databases. Therefore, though PERs 2 and 3 are nuclear proteins (Jin, X., et al., Cell 96, 57-68 (1999)), they apparently use alternative sequences and or mechanisms for their nuclear import.
- hPER1-MPP functions as a MPP in a variety of cell types.
- hPER1-MPP demonstrated intense focal staining in the nuclear plasma as well as in the nucleolus, suggesting that the subnuclear address of hPER1-MPP is different from the hPER1 (P1-FL) protein that was diffused in the nucleus but not concentrated in the nucleolus.
- any potential MPPs must be functionally determined experimentally.
- transducing or non-transducing proteins can encode MPP regions
- the interesting question that remains is whether or not proteins containing MPP-like sequences use these domains to rapidly translocate intracellularly into cellular domains to activate normal physiological processes.
- the efficiency associated with the transduction phenomena might be particularly useful where the rapid delivery of intercellular information is critical, as may be the case in cell synchronization, development, and differentiation paradigms.
- MPPs cargo molecules to intracellular compartments
- hPER1-MPP and other MPPs identified herein can deliver compounds of interest, such as large molecules, i.e., peptides and proteins, lipids, polysaccharides, other organic molecules, rapidly and efficiently into cells.
- hPER1-MPP in fusion with either serotonergic and/or adrenergic 7TM-receptor derived peptides mimic the effects of ligand activated receptors (see FIG. 4, and data not shown), confirming that hPER1-MPP translocates compounds of interest to intracellular compartments, and supports the idea that physiologically relevant signaling can be initiated by MPPs linked to compounds of interest.
- the present invention may be expanded to provide target validation using MPPs linked to targets, and/or therapeutic strategies using MPPs linked to specific enzymes or receptors as a method of altering, correcting or compensating for dysfunctional enzyme performance or within pathways.
- therapeutic strategies using MPPs linked to specific receptors may be used as a method of altering, correcting or compensating for dysfunctional receptor, low expression of normal or abnormal receptors.
- results provided herein demonstrate an MPP encoded by a mammalian protein and more specifically, a human nuclear protein, whose cellular penetration is membrane independent and likely depends on the peptide structure.
- hPER1-MPP targets to specific subnuclear sites, but has the potential to efficiently deliver other macromolecules to intracellular targets.
- this invention also provides the first example for mapping a novel MPP based on a NLS domain, and suggests that many MPP-like regions are contained within a wide variety of proteins.
- the data provided herein demonstrate that an MPP may be based on part of an NLS, or overlap with part of the NLS, or alternatively, may be a novel peptide.
- NLS sequences are well known in the art, and include NLSs previously identified as conferring the ability of the native protein to enter the nucleus, or is a putative NLS based on substantial sequence homology with a previously identified NLS.
- the NLS may be identified by sequence deletion experiments. See for example, Luo J C, Shibuva M A variant of nuclear localization signal of bipartite-type is required for the nuclear translocation of hypoxia inducible factors (1alpha, 2alpha and 3alpha). Oncogene. 2001 Mar 22;20(12):1435-44 or Hodel M R, Corbett A H, Hodel A E. Dissection of a nuclear localization signal. J Biol Chem. 2001 Jan 12;276(2):1317-25.
- Preferred membrane penetrating peptides are small polypeptides, and may be derived from an NLS, or overlapping with an NLS, of a mammalian or yeast protein.
- Preferred mammalian proteins are those of human, primate, murine or rat species. It is generally preferred to use the same species for the NLS-derived protein as the cell to be treated. Human species are especially preferred as the NLS-derived protein when being used to treat human cells.
- NLSs may be found within a broad class of enzymes, and is not limited to nuclear proteins, transcription factors, cytokines and kinases.
- Preferred MPPs are those derived from nuclear proteins or transcription factors.
- MPPs of the present invention are small polypeptides comprising a sequence —(X—X—X—X) n — where n is an integer 1 to 7, and X each time is independently selected from the group consisting of arginine, histidine or lysine. It is preferred that small MPPs are used, and therefore, it is preferred that n is an integer 1 to 5, and more preferred that n is an integer 1 to 3. Selected embodiments of suitable MPPs are provided in Table 1 and Example 5.
- the MPP and/or compound of interest may be chemically synthesized separately, for example, by chemical synthetic routes and using commercially available reagents.
- the MPP and/or compound of interest may be synthesized by recombinant technology and purified according to known methods. Host cells, cloning vectors, promoters and oligonucleotide linkers are well known and commercially available. Methodologies for using recombinant technology and purification methods are also well known, see Current Protocols in Molecular Biology, 4 Vols. Wiley. Generally, recombinant technology is preferred, as it is more amenable to larger scale production and is more economical for mass production. Alternatively, MMPs may be obtained by specific protease degradation of a precursor proteins.
- the compound of interest may be attached or linked to the MPP via chemical crosslinking at the N- or C-terminus of the MPP to create a conjugated (also referred to a a fusion) MPP and compound of interest, for example, via disulfide or ester linkages.
- the compound of interest is a peptide
- the peptide may be synthesized by recombinant technology with a host cell with an expression vector encoding a fusion of the MPP sequence and the compound of interest under conditions to permit expression of the vector and obtaining the fusion MPP and compound of interest.
- the MPP and the compound of interest may be attached or linked via a chemical linker.
- Chemical linkers are well known in the art, and include but are not limited to dicyclohexylcarbodiimide (DCC), N-hydroxysuccinimide (NHS), maleiimidobenzoyl-N-hydroxysuccinimide ester (MBS), N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ), N-isobutyloxy-carbonyl-2-isobutyloxy-1,2-dihydroquinoline (IIDQ).
- DCC dicyclohexylcarbodiimide
- NHS N-hydroxysuccinimide
- MBS maleiimidobenzoyl-N-hydroxysuccinimide ester
- EEDQ N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline
- IIDQ N-isobutyloxy-carbony
- Preferred linkers may also be monomeric entities such as a single amino acid, especially preferred are those amino acids with small side chains, or a small polypeptide chain, or polymeric entities of several amino acids.
- Preferred polypeptide linkers are fifteen amino acids or less, more preferred are polypeptide linkers of ten or less amino acids. Even more preferred are polypeptide linkers of five or less amino acids.
- the linker may be a nucleic acid encoding a small polypeptide chain; preferred linkers encode a polypeptide of fifteen or less amino acids. More preferred linkers are nucleic acids encoding a small polypeptide chains of ten or less amino acids. Even more preferred linkers are nucleic acid encoding a small polypeptide of five or less amino acids, such as Gly-Phe-Leu-Gly, Gly-Gly, Gly-Leu or Gly, and the like.
- Recombinant technology may be used to express a fusion MPP, linker and compound of interest, as described above and is well known in the art.
- the linker may be a cleavable linker, resulting in cleavage of the MPP and compound of interest once delivered to the tissue or cell of choice.
- the cell or tissue would have endogenous (either naturally occurring enzyme or be recombinantly engineered to express the enzyme) or have exogenous (e.g., by injection, absorption or the like) enzyme capable of cleaving the cleavable linker.
- Suitable enzymes for cleavage include, for example, use of a KEX2 protease recognition site (Lys, Arg) inserted between glucoamylase and the desired polypeptide to allow in vivo release of the desired polypeptide from the fusion protein as a result of the action of a native Aspergillus KEX2-like protease.
- a cleavable linker peptide comprises the recognition sequence Asp-Asp-Asp-Asp-Lys, and wherein said fusion protein is cleavable by enterokinase.
- the linker may be biodegradable such that the compound of interest is detached from the fusion MPP and compound of interest by hydrolysis and/or enzymatic cleavage inside cells.
- tumors often express specific proteases, and be used in the delivery of prodrugs of cytotoxic agents.
- the linker may be selective for lysosomal proteases, such as cathepsin B, C, or D. Delivery of prodrugs and their subsequent activation is well recognized, and such an approach provides significantly less systemic toxicity due to premature linker hydrolysis in the blood, consequently a greater amount of compound of interest, i.e., drug or cytotoxic agent, is delivered to the tumor site. See for example, T. Higuchi and V.
- Stella provide a thorough discussion of the prodrug concept in Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, American Chemical Society (1975).
- Examples of readily-cleavable groups include acetyl, trimethylacetyl, butanoyl, methyl succinoyl, t-butyl succinoyl, ethoxycarbonyl, methoxycarbonyl, benzoyl, 3-aminocyclohexylidenyl, and the like.
- the compound of interest is any organic molecule, and includes small organic molecules, peptides, lipoproteins, and other modified proteins, polysaccharides, oligonucleotides, antisense oligonucleotides, and any other compound thought to have pharmaceutical, prophylactic, diagnostic properties and/or research interest.
- the compound of interest may be a small organic molecule already known to have pharmaceutical properties, and thus the present invention may be used as a method of treating a patient with the compound of interest.
- the compound of interest may be a novel protein of unknown function, and thus the present invention may be used as a method of identifying the function of the compound of interest.
- the compound of interest may be an antisense molecule, and thus the present invention may be used as a method of altering transcription.
- the compound of interest may be a prodrug, e.g. in an inactive form but capable of being activated once within the cell.
- the compound of interest may be a cytotoxic agent, and thus the invention may be used as a method of delivering a cytotoxic agent to a cell.
- the compound of interest also includes detectable proteins which are useful to generate conjugated MMP and the detectable protein for identification of new MMPs. Detectable proteins include GFP, beta galactosidase, radiolabeled proteins and biotinylated proteins, proteins capable of conferring a detectable phenotype in the cell.
- the present invention may be used to deliver the compound of interest into a cell in vitro, ex vivo or in vivo.
- delivery may be carried out in vitro by adding the conjugated MPP and compound of interest extracellularly to cultured cells.
- Delivery may be carried out ex vivo by adding the conjugated MPP and compound of interest extracellularly or exogenously to a cultured sample removed from a patient, for example, blood, tissue or bone marrow, and returning the treated sample to the patient.
- Delivery may be carried out in vivo by administering the conjugated MPP and compound of interest by transdermal administration, inhalation, or injection to a patient.
- the cell may be of mammalian, bacterial, viral or yeast origin.
- the cell may be a cultured cell such as commonly used for oncology screening. Examples of cultured cells include CHO, HEK293T, HeLa, and NIH3T3.
- the cell may be a cultured cell from a patient suitable for ex vivo treatment with an MPP conjugate and reintroduction into a patient.
- the cell may be from the same or different patient than the patient to be treated.
- compositions of the invention comprising the conjugated MPP and compound of interest may be used for therapeutic, prophylactic, diagnostic or research purposes.
- Compositions may further comprise adjuvants, stabilizers and the like to improve the handling, stability and storage properties of the compositions.
- One method for identification of a membrane penetrating peptide is to generate a conjugate peptide comprising the sequence —(X—X—X—X) n — where n is an integer 1 to 7, and X each time is independently selected from the group consisting of arginine, histidine or lysine, with a detectable protein such as GFP, beta galactosidase and the like, adding the conjugate peptide to a cell and determining if the conjugated peptide is located within the cytoplasm and/or nucleus of the cell.
- Another method for identification of a membrane penetrating peptide is to generate a conjugate peptide comprising a peptide derived from or overlapping with a nuclear localization sequence of a mammalian or yeast protein and a detectable protein such as GFP, beta galactosidase and the like, adding the conjugate peptide to a cell and determining if the conjugated peptide is located within the cytoplasm and/or nucleus of the cell.
- A refers to Ala, or alanine
- C refers to Cys or cysteine
- D refers to Asp or aspartic acid
- E refers to Glu or glutamic acid
- F refers to Phe or phenylalanine
- G refers to Gly or glycine
- H refers to His or histidine
- I refers to Ile or isoleucine
- K refers to Lys or lysine
- L refers to Leu or leucine
- M refers to Met or methionine
- N refers to Asn or asparagine
- P refers to Pro or proline
- Q refers to Gln or glutamine
- R refers to Arg or arginine
- S refers to Ser or serine
- T refers to Thr or threonine
- V refers to Val or valine
- W refers to Trp or tryptophan
- Y refers to Tyr or tyrosine.
- v/v refers to volume to volume
- EYFP refers to a peptide fragment of the sequence Glu-Tyr-Phe-Pro
- ORF refers to Open Reading Frame
- PCR refers to polymerase chain reaction
- CHO refers to Chinese Hamster Ovary cells
- HHEK293T Human Embryonic Kidney cells
- HeLa refers to epithelial adenocarcinoma cells
- NIH3T3 refers to Swiss mouse embryo fibroblast cells
- DMSO refers to dimethyl sulfoxide
- FCS refers to fetal calf serum
- DMEM refers to Dulbecco's Modified Eagle's Medium
- PBS refers to Phosphate buffered saline
- BSA bovine serum albumin
- C-terminus refers to the carboxy-terminus
- N-terminus refers to the carboxy-terminus
- EYFP-hPer1 ORF, P1-N and P1-NX (FIG. 1A) is generated by insertion of EcoRI and XhoI digested fragments into EYFP-C1 vector (Clontech). The other fragments are PCR amplified from the full-length hPer1 cDNA and subcloned into EYFP-C1 vector. The first and the last residue present in each of fragment is indicated in FIG. 1A. All constructs are verified by automated DNA sequencing.
- CHO, HeLa and 293T cells are maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal calf serum (FCS), 50 units/ml penicillin, 50 ⁇ g streptomycin, and 4 mM L-glutamine (hereafter referred to as complete DMEM) at 37° C. with 5% CO 2 .
- DMEM Dulbecco's Modified Eagle's Medium
- FCS fetal calf serum
- penicillin 50 units/ml calf serum
- streptomycin 50 units/ml calf serum
- 4 mM L-glutamine hereafter referred to as complete DMEM
- Peptides are synthesized by a commercial vendor (Bio Synthesis). For peptides internalization, cells are plated into two-well Lab-Tek coverslips (Nunc Inc.) at a density of 2 ⁇ 10 5 cells/well and cultured overnight. The peptides are dissolved in DMSO diluted to indicated concentration with PBS. The cell monolayers were incubated with the appropriate peptide/PBS solution at 1 ⁇ M standard concentration for 10 min at room temperature (RT) unless otherwise specified. For experiments at 4° C., the protocol was the same except that all incubations were performed at 4° C. until the end of the fixation procedure.
- transfected cells were examined directly without fixation or after fixation with 4% (v/v) formaldehyde in PBS for 20 min at 4° C. and washed with PBS.
- fixation with 4% (v/v) formaldehyde in PBS for 20 min at 4° C. and washed with PBS.
- indirect immunodetection of biotinylated peptides fixed cell were washed twice with PBS and permeabilized with 0.3% Triton X-100 in PBS for 20 min at 4° C. and blocked with 2% BSA in PBS for 30 min at RT.
- construct P1-F1 has a strictly cytoplasmic localization pattern irrespective of the fact that it contains the NLS, supporting published observations that this region also contains and as yet unidentified cytoplasmic localization domain (Vielhaver, E., et al., Mol Cell Biol. 20, 4888-4899 (2000)).
- Sequence alignment shows that the hPER1-NLS is conserved between human and mouse PER1 proteins (FIG. 1A), but not with other putative NLSs, or with other human, mouse or Drosophila PERs.
- hPER1 is also a nuclear protein whose NLS is rich in basic amino acids (SRRHHCRSKAKRSRHH, see FIG. 1).
- the peptides are assayed for their ability to penetrate cellular membranes. Intracellular localization is assayed by direct staining with labeled Streptavidin ALEXA reagents or by indirect staining with anti-Flag mAb followed by the addition of labeled secondary antibodies. When added to the cells in culture at a concentration of 10 ⁇ M, hPER1-MPP, Flag-hPER1-MPP and Flag TAT-PTD peptides are found to penetrate rapidly into 100% cells (FIG. 2A and FIG. 5).
- hPER1-MPP, Flag-tagged hPER1-MPP, and Flag-tagged TAT-PTD are observed to be diffusely distributed throughout the cytoplasm, but concentrated within subnuclear domains that appear as distinct foci within the nucleoplasm and the nucleolus.
- biotinylated negative control peptides, Flag-Flag and several additional peptides derived from other hPER1 regions are only barely discernible background staining, with no staining in the nucleus or nucleoli, even at high concentrations (data not shown). Confocal microscopy is used to confirm the intracellular and intranuclear staining of Flag-tagged hPER1-MPP, and that the negative control peptides are not internalized (FIG. 2A).
- hPER1-MPP rapidly penetrated the cellular membranes and localized in nuclear regions with efficiencies similar to the TAT-PTD peptide (FIG. 2B). Identical results are obtained using CHO, HEK293T, HeLa, NIH3T3 and cultured rat primary cortical neurons (data not shown), indicating cell type-independent penetration.
- hPER1-MPP internalization occurs rapidly (within 5 min), with similar potencies at 4C. and 37C. and even after cell membrane fixation (data not shown).
- the amino acid sequence 830-845 of hPER1 functions as both as a protein nuclear/nucleolar localization signal in the fusion protein and as a MPP, and that membrane penetration is independent of traditional receptor-mediated endocytic mechanisms.
- Arginine 7 is Essential for hPER1-MPP Activity
- the arginine 7 residue plays a critical role in the cell penetrating ability of the hPER1-MPP.
- CHO cells transfected with fusion protein P1-R7A arginine 7 mutated to alanine
- nuclear staining similar to the wild-type, P1-NLS (data not shown).
- Nuclear translocation appears to be normal in the P1-R7A mutant fusion protein, but subnuclear targeting to the nucleoli is disrupted (data not shown).
- MPPs One of the features of MPPs is their ability to cargo proteins and peptides into cells.
- Fawells et al. 1994
- et al. Proc Natl Acad Sci USA. 91, 664-668 (1994)
- TM7 conserved transmembrane segment 7
- GPCR G-protein coupled receptor
- I3 the third intracellular loop (I3) plays a significant role in GPCR calcium signaling (Wess, J M., et al., EMBO J. 12, 331-338 (1993)) while intracellular loops 1 and 2 (I1 and I2) appear not to be important.
- 5HT2A we experimentally tested the ability of hPER1-MPP and TAT-PTD in fusion with peptides designed from I1 and the TM7 domains to activate the receptor.
- Biotinylated peptides hPER1-MPP TM7, TAT-PTD TM7, hPER1-MPP I1, TAT-PTD I1, hPER-MPP, TAT-PTD, TM7 or I1 were incubated at a concentration of 10 ⁇ M with a 5HT2A receptor CHO stable cell line. Peptide membrane penetration was assayed using Streptavidin-Alexa 594 as described above. As shown in FIG. 4A, receptor signaling is activated by the addition of exogenous serotonin, hPER1-MPP TM7, and TAT-PTD TM7 as measured by the level of the calcium response.
- TM7 alone nor any of the other peptides were able to generate a calcium response.
- the activation of the receptor by hPER1-MPP TM7 and TAT-PTD TM7 is peptide concentration dependent, FIG. 4B.
- the addition of increasing concentrations of the activating peptide, TM7, in fusion with hPER1-MPP or TAT-PTD results in a calcium response in a dose dependent manner.
- TAT-PTD TM7 appears to be a more potent 5HT2A receptor activator than is hPER1-MPP TM7.
- TAT-PTD TM7 is more cytoplasmically localized or has greater cell penetrating capabilities than hPER1-MPP TM7, although we have not observed that to be the case.
- Similar results were also obtained in this laboratory using hPER1-MPP in fusion with ⁇ -adrenergic activating peptides (unpublished data). These data support previous results that hPER1-MPP not only penetrates cell membranes, but also demonstrates that it is capable of cargoing peptides to intracellular compartments to initiate biologically relevant signal transduction events.
- hPER1 is a nuclear protein proposed to be involved in transcriptional regulation, and since, to date, all PTDs derived from naturally occurring proteins are transcription factors (TAT, Antp, and VP22), we sought to determine if other PTD sequences existed within the genome. To this end, we used two approaches; first, we searched the NCBI non-redundant protein database for all known and putative NLS's (table 1, 10-17). We synthesized peptides corresponding to the NLS amino acid sequences and assayed for peptide transduction. As shown in table 1 and FIG. 5, 6 of the 7 peptides synthesized had membrane penetrating characteristics similar to hPER-PTD and TAT-PTD.
- proteins included human proteins of the thyroid hormone receptor alpha-1, homeobox protein HME1, and proto-oncogene protein ABL-1. Furthermore, (table 1 and FIG. 5) when we create in frame fusion proteins between these peptide sequences and GFP then transfected into CHO or HEK 293T cells, all of the sequences conferred nuclear localization of the fusion protein.
- NLSs are PTDs as is apparent in SV40, hPER2, C-FOS, Cyclin L ania-6 and beta Zip transcription factor NLSs (table 1). These results also suggest that PTDs sequences are prevalent throughout the genome and in particular within nuclear proteins.
- At least one feature of HIV TAT transducing peptide is its ability to cargo proteins into cells and tissues. We therefore sought to determine if hPER1 transducing peptide could cargo beta galactosidase into cells.
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DE (1) | DE60133585T2 (pt) |
GB (1) | GB0103110D0 (pt) |
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Also Published As
Publication number | Publication date |
---|---|
IL154589A (en) | 2011-08-31 |
US7754678B2 (en) | 2010-07-13 |
AR033834A1 (es) | 2004-01-07 |
BRPI0113477B1 (pt) | 2019-10-22 |
KR20030034156A (ko) | 2003-05-01 |
DE60133585T2 (de) | 2009-06-04 |
ZA200301476B (en) | 2004-06-22 |
JP4896356B2 (ja) | 2012-03-14 |
TWI317737B (en) | 2009-12-01 |
US20060100134A1 (en) | 2006-05-11 |
KR100810927B1 (ko) | 2008-03-10 |
DE60133585D1 (de) | 2008-05-21 |
BRPI0113477B8 (pt) | 2021-05-25 |
JP2004512275A (ja) | 2004-04-22 |
BR0113477A (pt) | 2004-04-20 |
GB0103110D0 (en) | 2001-03-28 |
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