Inhibiting HIV Fusion with a β-Peptide Foldamer

Citations Over TimeTop 10% of 2005 papers

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.

Related Papers

• → Conserved and Exposed Epitopes on Intact, Native, Primary Human Immunodeficiency Virus Type 1 Virions of Group M(2000)141 cited
• → The Recombinant Immunogen with High‐Density Epitopes of ELDKWA and ELDEWA Induced Antibodies Recognizing Both Epitopes on HIV‐1 gp41(2005)13 cited
• → Human Antibodies that Recognize Novel Immunodominant Quaternary Epitopes on the HIV-1 Env Protein(2016)11 cited
• → Induction of high level of specific antibody response to the neutralizing epitope ELDKWA on HIV-1 gp41 by peptide-vaccine☆(2000)18 cited
• → Linear Epitopes of HIV-1, Presented as Hybrids with Escherichia Coli β-Galactosidase or Synthetic Peptides(1994)2 cited