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Peptide-Based Drug Design: Here and Now

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Peptide-Based Drug Design

Part of the book series: Methods In Molecular Biology™ ((MIMB,volume 494))

Summary

After many years of stagnation, peptide therapeutics once again became the focus of innovative drug development efforts backed up by venture funds and biotechnology companies. Designer peptide drugs overcome the unattractive pharmacological properties of native peptides and protein fragments and frequently feature nonnatural amino acid or backbone replacements, cyclic or multimeric structures, or peptidic or nonpeptidic delivery modules. With their high specificity and low toxicity profile, biologicals offer viable alternatives to small molecule therapeutics. The development of peptide drugs requires specific considerations of this family of biopolymers. Historically, peptide vaccines to viral infections and antibacterial peptides led the way in clinical development, but recently many other diseases have been targeted, including the big sellers AIDS, cancer, and Alzheimer’s disease. This book gives practical advice to the most important steps in peptide-based drug development such as isolation, purification, characterization, interaction with targets, structural analysis, stability studies, assessment of biodistribution and pharmacological parameters, sequence modifications, and high throughput screening. This brief overview provides historical background for each of the listed techniques and diseases.

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References

  1. Loffet, A. (2002) Peptides as drugs: Is there a market? J. Pept. Sci. 8, 1–7.

    Article  CAS  PubMed  Google Scholar 

  2. Ryser, H.J., and Fluckiger, R. (2005) Progress in targeting HIV-1 entry. Drug Discov. Today 10, 1085–1094.

    Article  CAS  PubMed  Google Scholar 

  3. Kazmierski, W.M., Kenakin, T.P., and Gudmundsson, K.S. (2006) Peptide, peptidomimetic and small molecule drug discovery targeting HIV-1 host-cell attachment and entry through gp120, gp41, CCR5 and CXCR4. Chem. Biol. Drug Des. 67, 13–26.

    Article  CAS  PubMed  Google Scholar 

  4. Mack, M., Luckow, B., Nelson, P.J., et al. (1998) Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J. Exp. Med. 187, 1215–1224.

    Article  CAS  PubMed  Google Scholar 

  5. Hartley, O., Gaertner, H., Wilken, J., et al. (2004) Medicinal chemistry applied to a synthetic protein: Development of highly potent HIV entry inhibitors. Proc. Natl. Acad. Sci. USA 101, 16460–16465.

    Article  CAS  PubMed  Google Scholar 

  6. Powell, M.F., Stewart, T., Otvos, L., Jr., et al. (1993) Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. Pharmacol. Res. 10, 1268–1273.

    Article  CAS  Google Scholar 

  7. Polt, R., Porreca, F., Szabo, L Z., et al. (1994). Glycopeptide enkephalin analogues produce analgesia in mice; evidence for penetration of the blood-brain barrier. Proc. Natl. Acad. Sci. USA 91, 7114–7118.

    Article  CAS  PubMed  Google Scholar 

  8. Egleton, R.D., Mitchell, S.A., Huber, J.D., et al. (2000) Improved bioavailability to the brain of glycosylated Met-enkephalin analogs. Brain Res. 881, 37–46.

    Article  CAS  PubMed  Google Scholar 

  9. Otvos, L., Jr., Cudic, M., Chua, B.Y., Deliyannis, G., and Jackson, D.C. (2004) An insect antibacterial peptide-based drug delivery system. Mol. Pharmaceut. 1, 220–232.

    Article  CAS  Google Scholar 

  10. Josserand, V., Pelerin, H., de Bruin, B., et al. (2006) Evaluation of drug penetration into the brain: a double study by in vivo imaging with positron emission tomography and using an in vitro model of the human blood-brain barrier. J. Pharmacol. Exp. Ther. 316, 79–86.

    Article  CAS  PubMed  Google Scholar 

  11. Werle, M. (2006) Innovations in oral peptide delivery. Future Drug Deliver.39–40.

    Google Scholar 

  12. Brogden, K.A. (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 3, 238–250.

    Article  CAS  PubMed  Google Scholar 

  13. Zasloff, M. (2002) Antimicrobial peptides of multicellular organisms. Nature 415, 389–395.

    Article  CAS  PubMed  Google Scholar 

  14. Cudic, M., Lockatell, C.V., Johnson, D.E., and Otvos, L., Jr. (2003) In vitro and in vivo activity of antibacterial peptide analogs against uropathogens. Peptides 24, 807–820.

    Article  CAS  PubMed  Google Scholar 

  15. Otvos, L., Jr. (2005) Antibacterial peptides and proteins with multiple cellular targets. J. Pept. Sci. 11, 697–706.

    Article  CAS  PubMed  Google Scholar 

  16. Bray, B.L. (2003) Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat. Rev. Drug Discovery 2, 587–593.

    Article  CAS  Google Scholar 

  17. Garber, K. (2005) Peptide leads new class of chronic pain drugs. Nat. Biotechnol. 23, 399.

    Article  CAS  PubMed  Google Scholar 

  18. Meloen, R., Timmerman, P., and Langedijk, H. (2004) Bioactive peptides based on diversity libraries, supramolecular chemistry and rational design; A class of peptide drugs. Introduction. Mol. Diversity 8, 57–59.

    Article  CAS  Google Scholar 

  19. Muderspach, L., Wilczynski, S., Roman, L., et al. (2000) A phase I trial of a human papillomavirus (HPV) peptide vaccine for women with high-grade cervical and vulvar intraepithelial neoplasia who are HPV 16 positive. Clin. Cancer Res. 6, 3406–3416.

    CAS  PubMed  Google Scholar 

  20. Agdeppa, E.D. (2004) Rational design for peptide drugs. J. Nucl. Med. 47, 22 N–24 N.

    Google Scholar 

  21. Backer, M.V., Levashova, Z., Patel, V., et al. (2007) Molecular imaging of VEGF receptors in angiogenic vasculature with single-chain VEGF-based probes. Nat. Med. 13, 504–509.

    Article  CAS  PubMed  Google Scholar 

  22. Arai, H., Lee, V.M.-Y., Otvos, L., Jr., et al. (1990) Defined neurofilament, tau and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques. Proc. Natl. Acad. Sci. USA 87, 2249–2253.

    Article  CAS  PubMed  Google Scholar 

  23. Hoffmann, R., Lee, V.M.Y., Leight, S., Varga, I., and Otvos, L., Jr. (1997) Unique Alzheimer’s disease paired helical filament specific epitopes involve double phosphorylation at specific sites. Biochemistry 36, 8114–8124.

    Article  CAS  PubMed  Google Scholar 

  24. Adessi, C., Frossard, M-J., Boissard, C., et al. (2003). Pharmacological profiles of peptide drug candidates for the treatment of Alzheimer’s disease. J. Biol. Chem. 278, 13905–13991.

    Article  CAS  PubMed  Google Scholar 

  25. Kotha, S., and Lahiri, K. (2005) Post-treatment assembly modifications by chemical methods. Curr. Med. Chem. 12, 849–875.

    Article  CAS  PubMed  Google Scholar 

  26. Sehgal, A. (2002) Recent development in peptide-based cancer therapeutics. Curr. Opin. Drug Discov. Devel. 5, 245–250.

    CAS  PubMed  Google Scholar 

  27. Borghouts, C., Kunz, C., and Groner, B. (2005) Current strategies for the development of peptide-based anti-cancer therapeutics. J. Pept. Sci. 11, 713–726.

    Article  CAS  PubMed  Google Scholar 

  28. Bruns, C., Lewis, I., Briner, U., Meno-Tetang, G., and Weckbecker, G. (2002) SOM230: a novel somatostatin petidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrin. 146, 707–716.

    Article  CAS  Google Scholar 

  29. Fedele, M., DeMartino, I., Pivonello, R., et al. (2007) SOM230, a new somatostatin analogue, is highly effective in the therapy of growth hormone/prolactin-secreting pituitary adenomas. Clin. Cancer Res. 13, 2738–2744.

    Article  CAS  PubMed  Google Scholar 

  30. Phan, J., Shi, Z-D., Burke, T.R., Jr., and Waugh, D.S. (2005) Crsytal structures of a high-affinity macrocyclic peptide mimetic complex with the Grb2 SH2 domain. J. Mol. Biol. 353, 104–115.

    Article  CAS  PubMed  Google Scholar 

  31. O, I., Otvos, L., Jr., Kieber-Emmons, T., and Blaszczyk-Thurin, M. (2002) Role of SA-Lea and E-selectin in metastasis assessed with peptide antagonist. Peptides 23, 999–1010.

    Article  PubMed  Google Scholar 

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© 2008 Humana Press a part of Springer Science+Business Media, LLC

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Otvos, L. (2008). Peptide-Based Drug Design: Here and Now. In: Otvos, L. (eds) Peptide-Based Drug Design. Methods In Molecular Biology™, vol 494. Humana Press. https://doi.org/10.1007/978-1-59745-419-3_1

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  • DOI: https://doi.org/10.1007/978-1-59745-419-3_1

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-990-1

  • Online ISBN: 978-1-59745-419-3

  • eBook Packages: Springer Protocols

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