Inhibiting HIV fusion with a beta-peptide foldamer.

Abstract

Linear peptides derived from the HIV gp41 C-terminus (C-peptides), such as the 36-residue Fuzeon, are potent HIV fusion inhibitors. These molecules bind to the N-peptide region of gp41 and inhibit an intramolecular protein-protein interaction that powers fusion of the viral and host cell membranes. The N-peptide region contains a surface pocket that is occupied in the post-fusion state by three alpha-helical residues found near the gp41 C-terminus: Trp628, Trp631, and Ile635-the WWI epitope. Here, we describe a set of beta3-decapeptides (betaWWI-1-4) in which the WWI epitope is presented on one face of a short 14-helix stabilized by macrodipole neutralization and side chain-side chain salt bridges. betaWWI-1-4 bind in vitro to IZN17, a validated gp41 model, and inhibit syncytia formation in cell culture. Molecules lacking a complete WWI functional epitope neither bind IZN17 nor inhibit syncytia formation. These results provide evidence that short beta-peptide 14-helices can inhibit an intramolecular protein-protein interaction in vivo. Molecules related to betaWWI-1-4 could represent starting points for the development of highly potent inhibitors or antigens effective against HIV or other viruses, including SARS, Ebola, HRSV, and influenza, that employ common fusion mechanisms.

• Authors: Olen M Stephens, Sunghwan Kim, Brett D Welch, Michael E Hodsdon, Michael S Kay, Alanna Schepartz
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 127 Issue 38 Pg. 13126-7 (Sep 28 2005) ISSN: 0002-7863 [Print] United States
• PMID: 16173723 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• HIV Fusion Inhibitors
• Oligopeptides

Topics

• Cell Fusion
• HIV Fusion Inhibitors (chemistry, pharmacology)
• HIV-1 (drug effects)
• HeLa Cells
• Humans
• Oligopeptides (chemical synthesis, chemistry, pharmacology)