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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<jats:sub>50<\/jats:sub>) of \u223c2 nM, with a selectivity index (50% cytotoxic concentration\/EC<jats:sub>50<\/jats:sub>) of \u223c2,000. 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.<\/jats:p>","DOI":"10.1128\/aac.00984-08","type":"journal-article","created":{"date-parts":[[2008,12,23]],"date-time":"2008-12-23T02:09:06Z","timestamp":1229998146000},"page":"1194-1203","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":50,"title":["Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase"],"prefix":"10.1128","volume":"53","author":[{"given":"Gregg S.","family":"Jones","sequence":"first","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Yu","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ameneh","family":"Zeynalzadegan","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Hesselgesser","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowu","family":"Chen","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Chen","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haolun","family":"Jin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Choung U.","family":"Kim","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Wright","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Romas","family":"Geleziunas","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Tsiang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.31.10.1613"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.67.11.6863-6865.1993"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/87979"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.04.054"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1981.tb06218.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0065-2571(84)90007-4"},{"key":"e_1_3_2_8_2","first-page":"103","year":"2007","unstructured":"Cooper, D. 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