title: A covalent inhibitor targeting an intermediate conformation of the fusogenic subunit of the HIV-1 envelope complex.
abstract: Peptide inhibitors corresponding to sequences in the six helix bundle structure of the fusogenic portion (gp41) of the HIV envelope glycoprotein have been successfully implemented in preventing HIV entry. These peptides bind to regions in HIV gp41 transiently exposed during the fusion reaction. In an effort to improve upon these entry inhibitors, we have successfully designed and tested peptide analogs composed of chemical spacers and reactive moieties positioned strategically to facilitate covalent attachment. Using a temperature-arrested state prime wash in vitro assay we show evidence for the trapping of a pre-six helix bundle fusion intermediate by a covalent reaction with the specific anti-HIV-1 peptide. This is the first demonstration of the trapping of an intermediate conformation of a viral envelope glycoprotein during the fusion process that occurs in live cells. The permanent specific attachment of the covalent inhibitor is projected to improve the pharmacokinetics of administration in vivo and thereby improve the long-term sustainability of peptide entry inhibitor therapy and help to expand its applicability beyond salvage therapy.
authors.affiliation: Center for Cancer Research Nanobiology Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Jacobs
authors.forename: Omar
authors.initials: O
authors.lastname: Quraishi
authors.forename: Xicai
authors.initials: X
authors.lastname: Huang
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bousquet-Gagnon
authors.forename: Geneviève
authors.initials: G
authors.lastname: Nault
authors.forename: Nicholas
authors.initials: N
authors.lastname: Francella
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Nga
authors.initials: N
authors.lastname: Pham
authors.forename: Chantal
authors.initials: C
authors.lastname: Soucy
authors.forename: Martin
authors.initials: M
authors.lastname: Robitaille
authors.forename: Dominique
authors.initials: D
authors.lastname: Bridon
authors.forename: Robert
authors.initials: R
authors.lastname: Blumenthal
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides