title: New small-molecule inhibitor class targeting human immunodeficiency virus type 1 virion maturation.
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.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 921212, USA.
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Joan
authors.initials: J
authors.lastname: Cao
authors.forename: Juin
authors.initials: J
authors.lastname: Fok-Seang
authors.forename: Paul
authors.initials: P
authors.lastname: Griffin
authors.forename: Jason
authors.initials: J
authors.lastname: Isaacson
authors.forename: R Lynn
authors.initials: RL
authors.lastname: Jackson
authors.forename: Edward
authors.initials: E
authors.lastname: Murray
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Peng
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.forename: Chris
authors.initials: C
authors.lastname: Pickford
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Scott L
authors.initials: SL
authors.lastname: Butler
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D036022:Capsid Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D014771:Virion / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D036022:Capsid Proteins