{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:12:46Z","timestamp":1783444366925,"version":"3.54.6"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T00:00:00Z","timestamp":1712102400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2024,4,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Protease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted once-daily oral dosing potential due to improvements in its metabolic stability and its pharmacokinetic properties in preclinical animal species. This compound demonstrates potent inhibitory activity and high on-target selectivity for recombinant HIV-1 protease versus other aspartic proteases tested. In cell culture, GS-9770 inhibits Gag polyprotein cleavage and shows nanomolar anti-HIV-1 potency in primary human cells permissive to HIV-1 infection and against a broad range of HIV subtypes. GS-9770 demonstrates an improved resistance profile against a panel of patient-derived HIV-1 isolates with resistance to atazanavir and darunavir. In resistance selection experiments, GS-9770 prevented the emergence of breakthrough HIV-1 variants at all fixed drug concentrations tested and required multiple protease substitutions to enable outgrowth of virus exposed to escalating concentrations of GS-9770. This compound also remained fully active against viruses resistant to drugs from other antiviral classes and showed no\n              <jats:italic>in vitro<\/jats:italic>\n              antagonism when combined pairwise with drugs from other antiretroviral classes. Collectively, these preclinical data identify GS-9770 as a potent, non-peptidomimetic once-daily oral HIV PI with potential to overcome the persistent requirement for pharmacological boosting with this class of antiretroviral agents.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01373-23","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T14:00:21Z","timestamp":1708524021000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5631-7459","authenticated-orcid":false,"given":"Andrew","family":"Mulato","sequence":"first","affiliation":[{"name":"Department of Virology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Lansdon","sequence":"additional","affiliation":[{"name":"Department of Structural Biology and Chemistry, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Voigt","sequence":"additional","affiliation":[{"name":"Department of Structural Biology and Chemistry, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Liclican","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Singer","sequence":"additional","affiliation":[{"name":"Department of Virology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Stafford","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyu","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Drug Metabolism, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yili","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shekeba","family":"Ahmadyar","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aesop","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George J.","family":"Stepan","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uli","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Department of Structural Biology and Chemistry, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Schultz","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Marchand","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Brumshtein","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Discovery Sciences and Technology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Cihlar","sequence":"additional","affiliation":[{"name":"Department of Virology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianhong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4444-7483","authenticated-orcid":false,"given":"Stephen R.","family":"Yant","sequence":"additional","affiliation":[{"name":"Department of Virology, Gilead Sciences, Foster City, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","volume-title":"WHO pharmaceuticals newsletter, No.3. 2021","year":"2021","unstructured":"2021. WHO pharmaceuticals newsletter, No.3. 2021"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1080\/00365519209104650"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.13.4686"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.02198-21"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200746090-00002"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1177\/135965350801300702"},{"key":"e_1_3_4_8_2","unstructured":"Department for Health and Human Services (DHHS). 2023. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. Available from: https:\/\/clinicalinfo.hiv.gov\/en\/guidelines\/perinatal\/recommendations-arv-drugs-pregnancy-overview. Accessed 20 Jul 2023."},{"key":"e_1_3_4_9_2","first-page":"1","volume-title":"Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach","author":"World health Organization (WHO)","year":"2021","unstructured":"World health Organization (WHO). 2021. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, p 1\u2013594"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm901408p"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm901414e"},{"key":"e_1_3_4_12_2","first-page":"9","article-title":"Analysis of combinations of antiviral drugs and design of effective multidrug therapies","volume":"1","author":"Prichard MN","year":"1996","unstructured":"Prichard MN, Shipman Jr C. 1996. Analysis of combinations of antiviral drugs and design of effective multidrug therapies. Antivir Ther 1:9\u201320.","journal-title":"Antivir Ther"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.2c08279"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-15-72"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.07.073"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909047337"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444909052925"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444904019158"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01474-16"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17180"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01215-07"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02057-20"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01183-10"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471220639.ch8"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0560-x"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.4.920-928.2000"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2443-1"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00289-10"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-29517-9"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c00071"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26760-4"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.121.000784"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm401499g"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01373-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/aac.01373-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T13:11:26Z","timestamp":1712149886000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/aac.01373-23"}},"subtitle":[],"editor":[{"given":"Miguel Angel","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,4,3]]},"references-count":32,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4,3]]}},"alternative-id":["10.1128\/aac.01373-23"],"URL":"https:\/\/doi.org\/10.1128\/aac.01373-23","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,3]]},"assertion":[{"value":"2023-10-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01373-23"}}