Chimica Oggi-Chemistry Today
Agro FOOD Industry Hi Tech
Hydrocarbon stapled peptides
Chemical and Peptide Products, AAPPTec, LLC

KEYWORDS: Stapled peptide, alpha-helix, protease resistance.

Hydrocarbon stapled peptides have important potential in the development of peptide drugs. Peptides have high potency, high specificity and few side effects, but are rapidly degraded by protease enzymes.  The hydrocarbon cross links of stapled peptides constrain the peptide in an a-helix conformation, favoring binding for peptides that bind to their receptor in an a-helix conformation.  Additionally, in a helical structure, the polar amide backbone is less exposed producing greater resistance to protease enzymes and increased penetration of cell membranes.   Double stapling of an HIV-1 fusion inhibitor greatly improved its pharmacokinetic properties, including oral availability. (1)

Gregory L. Verdine and coworkers reported the first hydrocarbon stapled peptides and their protease resistance. (2) Soon after, stapled peptides that inhibited the growth of human leukemia xenografts were reported. (3) These stapled peptides are potential leads to new cancer treatments.  
Stapled peptides provide new antiviral drug leads.  Stapled peptides targeting HIV-1 entry and assembly (4) are reported.  Hepatitis C virus infection can be inhibited by stapled peptides that disrupt binding of the virus envelope (5) and a double stapled respiratory syncytial virus peptide prevents nasopulmonary RSV infection in mice. (6)
Stapled vasoactive intestinal peptide derivatives improve glucose-dependent insulin secretion. (7) Stapled apolipoprotein mimetics promote cholesterol efflux from cells, making them interesting leads for therapeutic agents for cardiovascular disease. (8) A stapled analog of antimicrobial peptide esculentin-2EM displaying activity with increased protease resistance (9)  may lead to a new class of peptide antibiotics.

Stapled peptides are potential leads for more potent and effective pharmaceuticals, more potent and selective agonists and antagonists for studying receptors and biochemical signaling, and potential probes to study protein-protein interactions.


  1. G.H. Bird, N. Madani, A.F. Perry, A.M. Princiotto,J.G. Supko, X. He, E. Gavathiotis, J.G. Sodroski, L.D. Walensky, Proc. Natl. Acad. Sci. USA, 2010, 107, 14093-8.
  2. C.E. Schafmeister, J. Po, G.L. Verdine, J. Am. Chem. Soc., 2000, 122, 5891-2.
  3. L.D. Walensky, A.L. Kung, I. Escher, T.J. Malia, S. Barbuto, R.D. Wright, G. Wagner, G.L. Verdine, S.J. Korsmeyer, Science, 2004, 305, 1466-70.
  4. a)H. Zhang, F. Curreli, A.A. Waheed, P.Y. Mercredi, M. Mehta, P. Bhargava, D. Scacalossi,X. Tong, S. Lee, A. Cooper, M.F. Summers, E.O. Freed, Retrovirology, 2013, 10, 136; b) H. Zhang, F. Curreli, X. Zhang, S Bhattacharya, A.A. Waheed, A. Cooper, D. Cowburn, E.O. Freed, A.K. Debnath, Retrovirology, 2011, 8, 28.
  5. H-K Cui, J. Qing, Y. Guo, Y-J. Wang, L.-J. Cui, T.-H. He, L. Zhang, L. Liu, Bioorg. Med. Chem., 2013, 21, 3547-54.
  6. G.H. Bird, S. Boyapalle, T. Wong, K. Opoku-Nsiah, R. Bedi, W.C. Crannell, A.F. Perry, H. Nguyen, V. Sampayo, A....In order to continue reading this article please register to our website – registration is for free and no fees will be applied afterwards to download contents.

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