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New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.

Authors
  • Blair, Wade S1
  • Cao, Joan
  • Fok-Seang, Juin
  • Griffin, Paul
  • Isaacson, Jason
  • Jackson, R Lynn
  • Murray, Edward
  • Patick, Amy K
  • Peng, Qinghai
  • Perros, Manos
  • Pickford, Chris
  • Wu, Hua
  • Butler, Scott L
  • 1 Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 921212, USA.
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Publication Date
December 2009
Volume
53
Issue
12
Pages
5080–5087
Identifiers
DOI: 10.1128/AAC.00759-09
PMID: 19805571
Source
Medline
License
Unknown

Abstract

A new small-molecule inhibitor class that targets virion maturation was identified from a human immunodeficiency virus type 1 (HIV-1) antiviral screen. PF-46396, a representative molecule, exhibits antiviral activity against HIV-1 laboratory strains and clinical isolates in T-cell lines and peripheral blood mononuclear cells (PBMCs). PF-46396 specifically inhibits the processing of capsid (CA)/spacer peptide 1 (SP1) (p25), resulting in the accumulation of CA/SP1 (p25) precursor proteins and blocked maturation of the viral core particle. Viral variants resistant to PF-46396 contain a single amino acid substitution in HIV-1 CA sequences (CAI201V), distal to the CA/SP1 cleavage site in the primary structure, which we demonstrate is sufficient to confer significant resistance to PF-46396 and 3-O-(3',3'-dimethylsuccinyl) betulinic acid (DSB), a previously described maturation inhibitor. Conversely, a single amino substitution in SP1 (SP1A1V), which was previously associated with DSB in vitro resistance, was sufficient to confer resistance to DSB and PF-46396. Further, the CAI201V substitution restored CA/SP1 processing in HIV-1-infected cells treated with PF-46396 or DSB. Our results demonstrate that PF-46396 acts through a mechanism that is similar to DSB to inhibit the maturation of HIV-1 virions. To our knowledge, PF-46396 represents the first small-molecule HIV-1 maturation inhibitor that is distinct in chemical class from betulinic acid-derived maturation inhibitors (e.g., DSB), demonstrating that molecules of diverse chemical classes can inhibit this mechanism.

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