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Notably, antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of GS-9148. Viruses carrying four or more thymidine analog mutations showed a substantially smaller change in GS-9148 activity relative to that observed with most marketed NRTIs. GS-9131, an ethylalaninyl phosphonoamidate prodrug designed to maximize the intracellular delivery of GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells, GS-9131 is readily hydrolyzed to GS-9148, which is further phosphorylated to its active diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008). GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (<jats:italic>K<jats:sub>i<\/jats:sub><\/jats:italic>= 0.8 \u03bcM) and exhibits low inhibitory potency against host polymerases including DNA polymerase \u03b3. Oral administration of GS-9131 to beagle dogs at a dose of 3 mg\/kg of body weight resulted in high and persistent levels of GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of &gt;9 \u03bcM and a half-life of &gt;24 h). This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.<\/jats:p>","DOI":"10.1128\/aac.01215-07","type":"journal-article","created":{"date-parts":[[2007,12,4]],"date-time":"2007-12-04T01:34:37Z","timestamp":1196732077000},"page":"655-665","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":88,"title":["Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131"],"prefix":"10.1128","volume":"52","author":[{"given":"Tomas","family":"Cihlar","sequence":"first","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian S.","family":"Ray","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constantine G.","family":"Boojamra","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hon","family":"Hui","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genevieve","family":"Laflamme","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer E.","family":"Vela","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Grant","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Chen","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Myrick","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Durham, North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten L.","family":"White","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Gao","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuei-Ying","family":"Lin","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet L.","family":"Douglas","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil T.","family":"Parkin","sequence":"additional","affiliation":[{"name":"Monogram Biosciences, South San Francisco, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Carey","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rowchanak","family":"Pakdaman","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L.","family":"Mackman","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Foster City, California"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/095632020501600502"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.3.716-723.2002"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00968-06"},{"key":"e_1_3_2_5_2","unstructured":"Bioorg. 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