title: GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.
abstract: Insertions in the protease (PR) region of human immunodeficiency virus (HIV) represent an interesting mechanism of antiviral resistance against HIV PR inhibitors (PIs). Here, we demonstrate the improved ability of a phosphonate-containing experimental HIV PI, GS-8374, relative to that of other PIs, to effectively inhibit patient-derived recombinant HIV strains bearing PR insertions and numerous other mutations. We correlate enzyme inhibition with the catalytic activities of corresponding recombinant PRs in vitro and provide a biochemical and structural analysis of the PR-inhibitor complex.
authors.affiliation: Gilead Sciences and IOCB Research Center, Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Klára
authors.initials: K
authors.lastname: Grantz Šašková
authors.forename: Milan
authors.initials: M
authors.lastname: Kozíšek
authors.forename: Kirsten
authors.initials: K
authors.lastname: Stray
authors.forename: Dorien
authors.initials: D
authors.lastname: de Jong
authors.forename: Pavlína
authors.initials: P
authors.lastname: Rezáová
authors.forename: Jirí
authors.initials: J
authors.lastname: Brynda
authors.forename: Noortje M
authors.initials: NM
authors.lastname: van Maarseveen
authors.forename: Monique
authors.initials: M
authors.lastname: Nijhuis
authors.forename: Tomáš
authors.initials: T
authors.lastname: Cihlár
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D016254:Mutagenesis, Insertional; D063065:Organophosphonates / Q000032:analysis
chemical_list: D017320:HIV Protease Inhibitors; D063065:Organophosphonates; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1