title: HIV capsid is a tractable target for small molecule therapeutic intervention.
abstract: Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California, United States of America.
authors.forename: Wade S
authors.initials: WS
authors.lastname: Blair
authors.forename: Chris
authors.initials: C
authors.lastname: Pickford
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Irving
authors.forename: David G
authors.initials: DG
authors.lastname: Brown
authors.forename: Marie
authors.initials: M
authors.lastname: Anderson
authors.forename: Richard
authors.initials: R
authors.lastname: Bazin
authors.forename: Joan
authors.initials: J
authors.lastname: Cao
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ciaramella
authors.forename: Jason
authors.initials: J
authors.lastname: Isaacson
authors.forename: Lynn
authors.initials: L
authors.lastname: Jackson
authors.forename: Rachael
authors.initials: R
authors.lastname: Hunt
authors.forename: Anne
authors.initials: A
authors.lastname: Kjerrstrom
authors.forename: James A
authors.initials: JA
authors.lastname: Nieman
authors.forename: Amy K
authors.initials: AK
authors.lastname: Patick
authors.forename: Manos
authors.initials: M
authors.lastname: Perros
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Scott
authors.forename: Kevin
authors.initials: K
authors.lastname: Whitby
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Scott L
authors.initials: SL
authors.lastname: Butler
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002460:Cell Line; D018360:Crystallography, X-Ray; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D054298:Human Immunodeficiency Virus Proteins; D006801:Humans; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D036022:Capsid Proteins; D054298:Human Immunodeficiency Virus Proteins