title: Preclinical evaluation of GS-9160, a novel inhibitor of human immunodeficiency virus type 1 integrase.
abstract: GS-9160 is a novel and potent inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase (IN) that specifically targets the process of strand transfer. It is an authentic inhibitor of HIV-1 integration, since treatment of infected cells results in an elevation of two-long terminal repeat circles and a decrease of integration junctions. GS-9160 has potent and selective antiviral activity in primary human T lymphocytes producing a 50% effective concentration (EC(50)) of approximately 2 nM, with a selectivity index (50% cytotoxic concentration/EC(50)) of approximately 2,000. The antiviral potency of GS-9160 decreased by 6- to 10-fold in the presence of human serum. The antiviral activity of GS-9160 is synergistic in combination with representatives from three different classes of antiviral drugs, namely HIV-1 protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Viral resistance selections performed with GS-9160 yielded a novel pattern of mutations within the catalytic core domain of IN; E92V emerged initially, followed by L74M. While E92V as a single mutant conferred 12-fold resistance against GS-9160, L74M had no effect as a single mutant. Together, these mutations conferred 67-fold resistance to GS-9160, indicating that L74M may potentiate the resistance caused by E92V. The pharmacokinetic profile of GS-9160 in healthy human volunteers revealed that once-daily dosing was not likely to achieve antiviral efficacy; hence, the clinical development of this compound was discontinued.
authors.affiliation: Gilead Sciences, Foster City, California 94404, USA.
authors.forename: Gregg S
authors.initials: GS
authors.lastname: Jones
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.forename: Ameneh
authors.initials: A
authors.lastname: Zeynalzadegan
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesselgesser
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Chen
authors.forename: James
authors.initials: J
authors.lastname: Chen
authors.forename: Haolun
authors.initials: H
authors.lastname: Jin
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
authors.forename: Matthew
authors.initials: M
authors.lastname: Wright
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Manuel
authors.initials: M
authors.lastname: Tsiang
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D020134:Catalytic Domain / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009154:Mutation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D019427:HIV Integrase