title: Antiviral inhibition of the HIV-1 capsid protein.
abstract: During the assembly stage of the human immunodeficiency virus (HIV) replication cycle, several thousand copies of the viral Gag polyprotein associate at the cell membrane and bud to form an immature, non-infectious virion. Gag is subsequently cleaved by the protease, which liberates the capsid proteins for assembly into the polyprotein shell of the central core particle (or capsid) of the mature virus. Viral infectivity is critically dependent on capsid formation and stability, making the capsid protein a potentially attractive antiviral target. We have identified compounds that bind to an apical site on the N-terminal domain of the HIV-1 capsid protein and inhibit capsid assembly in vitro. One compound, N-(3-chloro-4-methylphenyl)-N'-[2-[([5-[(dimethylamino)-methyl]-2-furyl]-methyl)-sulfanyl]ethyl]urea) (CAP-1), is well tolerated in cell cultures, enabling in vivo antiviral and mechanistic studies. CAP-1 inhibits HIV-1 infectivity in a dose-dependent manner, but does not interfere with viral entry, reverse transcription, integration, proteolytic processing, or virus production, indicating a novel antiviral mechanism. Significantly, virus particles generated in the presence of CAP-1 exhibit heterogeneous sizes and abnormal core morphologies, consistent with inhibited CA-CA interactions during virus assembly and maturation. These findings lay the groundwork for the development of assembly inhibitors as a new class of therapeutic agents for the treatment of AIDS.
authors.affiliation: Howard Hughes Medical Institute and Department of Chemistry and Biochemistry, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250-5398, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Tang
authors.forename: Erin
authors.initials: E
authors.lastname: Loeliger
authors.forename: Isaac
authors.initials: I
authors.lastname: Kinde
authors.forename: Samson
authors.initials: S
authors.lastname: Kyere
authors.forename: Keith
authors.initials: K
authors.lastname: Mayo
authors.forename: Eric
authors.initials: E
authors.lastname: Barklis
authors.forename: Yongnian
authors.initials: Y
authors.lastname: Sun
authors.forename: Mingjun
authors.initials: M
authors.lastname: Huang
authors.forename: Michael F
authors.initials: MF
authors.lastname: Summers
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D015153:Blotting, Western; D002213:Capsid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity; D006801:Humans; D008854:Microscopy, Electron; D008958:Models, Molecular; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D013457:Sulfur Compounds; D014774:Virulence
chemical_list: D019380:Anti-HIV Agents; D005663:Furans; C473485:N-(3-chloro-4-methylphenyl)-N'-(2-(((5-((dimethylamino)-methyl)-2-furyl)-methyl)-sulfanyl)ethyl)urea; D010671:Phenylurea Compounds; D013457:Sulfur Compounds