A covalent inhibitor targeting an intermediate conformation of the fusogenic subunit of the HIV-1 envelope complex.
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.
Jacobs
Amy
A
Center for Cancer Research Nanobiology Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Quraishi
Omar
O
Huang
Xicai
X
Bousquet-Gagnon
Nathalie
N
Nault
Geneviève
G
Francella
Nicholas
N
Alvord
W Gregory
WG
Pham
Nga
N
Soucy
Chantal
C
Robitaille
Martin
M
Bridon
Dominique
D
Blumenthal
Robert
R
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
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides