{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T09:18:19Z","timestamp":1777540699290,"version":"3.51.4"},"reference-count":34,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["GM53386"],"award-info":[{"award-number":["GM53386"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            We identified four novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-078, -079, -077, and -058, containing an alkylamine at the C-5 position of P2 tetrahydropyrano-tetrahydrofuran (Tp-THF) and a P2\u2032 cyclopropyl (Cp) (or isopropyl)-aminobenzothiazole (Abt) moiety. Their 50% effective concentrations (EC\n            <jats:sub>50<\/jats:sub>\n            s) were 2.5 to 30 nM against wild-type HIV-1\n            <jats:sub>NL4-3<\/jats:sub>\n            , 0.3 to 6.7 nM against HIV-2\n            <jats:sub>EHO<\/jats:sub>\n            , and 0.9 to 90 nM against laboratory-selected PI-resistant HIV-1 and clinical HIV-1 variants resistant to multiple FDA-approved PIs (HIV\n            <jats:sub>MDR<\/jats:sub>\n            ). GRL-078, -079, -077, and -058 also effectively blocked the replication of HIV-1 variants highly resistant to darunavir (DRV) (HIV\n            <jats:sub>DRV<\/jats:sub>\n            <jats:sup>r<\/jats:sup>\n            <jats:sub>p51<\/jats:sub>\n            ), with EC\n            <jats:sub>50<\/jats:sub>\n            s of 38, 62, 61, and 90 nM, respectively, while four FDA-approved PIs examined (amprenavir, atazanavir, lopinavir [LPV], and DRV) had virtually no activity (EC\n            <jats:sub>50<\/jats:sub>\n            s of &gt;1,000 nM) against HIV\n            <jats:sub>DRV<\/jats:sub>\n            <jats:sup>r<\/jats:sup>\n            <jats:sub>p51<\/jats:sub>\n            . Structurally, GRL-078, -079, and -058 form strong hydrogen bond interactions between Tp-THF modified at C-5 and Asp29\/Asp30\/Gly48 of wild-type protease, while the P2\u2032 Cp-Abt group forms strong hydrogen bonds with Asp30\u2032. The Tp-THF and Cp-Abt moieties also have good nonpolar interactions with protease residues located in the flap region. For selection with LPV and DRV by use of a mixture of 11 HIV\n            <jats:sub>MDR<\/jats:sub>\n            strains (HIV\n            <jats:sub>11MIX<\/jats:sub>\n            ), HIV\n            <jats:sub>11MIX<\/jats:sub>\n            became highly resistant to LPV and DRV over 13 to 32 and 32 to 41 weeks, respectively. However, for selection with GRL-079 and GRL-058, HIV\n            <jats:sub>11MIX<\/jats:sub>\n            failed to replicate at &gt;0.08 \u03bcM and &gt;0.2 \u03bcM, respectively. Thermal stability results supported the highly favorable anti-HIV-1 potency of GRL-079 as well as other PIs. The present data strongly suggest that the P2 Tp-THF group modified at C-5 and the P2\u2032 Abt group contribute to the potent anti-HIV-1 profiles of the four PIs against HIV-1\n            <jats:sub>NL4-3<\/jats:sub>\n            and a wide spectrum of HIV\n            <jats:sub>MDR<\/jats:sub>\n            strains.\n          <\/jats:p>","DOI":"10.1128\/aac.02060-17","type":"journal-article","created":{"date-parts":[[2018,2,15]],"date-time":"2018-02-15T10:07:58Z","timestamp":1518689278000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":9,"title":["GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants"],"prefix":"10.1128","volume":"62","author":[{"given":"Nicole S.","family":"Delino","sequence":"first","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"name":"Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manabu","family":"Aoki","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironori","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin-ichiro","family":"Hattori","sequence":"additional","affiliation":[{"name":"Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon B.","family":"Chang","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuki","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuthbert D.","family":"Martyr","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, Indiana, USA"},{"name":"Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana, 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