{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:41:57Z","timestamp":1780515717360,"version":"3.54.1"},"reference-count":60,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T00:00:00Z","timestamp":1456790400000},"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":["J Virol"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            We identified three nonpeptidic HIV-1 protease inhibitors (PIs), GRL-015, -085, and -097, containing tetrahydropyrano-tetrahydrofuran (Tp-THF) with a C-5 hydroxyl. The three compounds were potent against a wild-type laboratory HIV-1 strain (HIV-1\n            <jats:sup>WT<\/jats:sup>\n            ), with 50% effective concentrations (EC\n            <jats:sub>50<\/jats:sub>\n            s) of 3.0 to 49 nM, and exhibited minimal cytotoxicity, with 50% cytotoxic concentrations (CC\n            <jats:sub>50<\/jats:sub>\n            ) for GRL-015, -085, and -097 of 80, &gt;100, and &gt;100 \u03bcM, respectively. All the three compounds potently inhibited the replication of highly PI-resistant HIV-1 variants selected with each of the currently available PIs and recombinant clinical HIV-1 isolates obtained from patients harboring multidrug-resistant HIV-1 variants (HIV\n            <jats:sub>MDR<\/jats:sub>\n            ). Importantly, darunavir (DRV) was &gt;1,000 times less active against a highly DRV-resistant HIV-1 variant (HIV-1\n            <jats:sub>\n              DRV\n              <jats:sup>R<\/jats:sup>\n            <\/jats:sub>\n            <jats:sub>P51<\/jats:sub>\n            ); the three compounds remained active against HIV-1\n            <jats:sub>\n              DRV\n              <jats:sup>R<\/jats:sup>\n            <\/jats:sub>\n            <jats:sub>P51<\/jats:sub>\n            with only a 6.8- to 68-fold reduction. Moreover, the emergence of HIV-1 variants resistant to the three compounds was considerably delayed compared to the case of DRV. In particular, HIV-1 variants resistant to GRL-085 and -097 did not emerge even when two different highly DRV-resistant HIV-1 variants were used as a starting population. In the structural analyses, Tp-THF of GRL-015, -085, and -097 showed strong hydrogen bond interactions with the backbone atoms of active-site amino acid residues (Asp29 and Asp30) of HIV-1 protease. A strong hydrogen bonding formation between the hydroxyl moiety of Tp-THF and a carbonyl oxygen atom of Gly48 was newly identified. The present findings indicate that the three compounds warrant further study as possible therapeutic agents for treating individuals harboring wild-type HIV and\/or HIV\n            <jats:sub>MDR<\/jats:sub>\n            .\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Darunavir (DRV) inhibits the replication of most existing multidrug-resistant HIV-1 strains and has a high genetic barrier. However, the emergence of highly DRV-resistant HIV-1 strains (HIV\n            <jats:sub>\n              DRV\n              <jats:sup>R<\/jats:sup>\n            <\/jats:sub>\n            ) has recently been observed\n            <jats:italic>in vivo<\/jats:italic>\n            and\n            <jats:italic>in vitro<\/jats:italic>\n            . Here, we identified three novel HIV-1 protease inhibitors (PIs) containing a tetrahydropyrano-tetrahydrofuran (Tp-THF) moiety with a C-5 hydroxyl (GRL-015, -085, and -097) which potently suppress the replication of HIV\n            <jats:sub>\n              DRV\n              <jats:sup>R<\/jats:sup>\n            <\/jats:sub>\n            . Moreover, the emergence of HIV-1 strains resistant to the three compounds was considerably delayed compared to the case of DRV. The C-5 hydroxyl formed a strong hydrogen bonding interaction with the carbonyl oxygen atom of Gly48 of protease as examined in the structural analyses. Interestingly, a compound with Tp-THF lacking the hydroxyl moiety substantially decreased activity against HIV\n            <jats:sub>\n              DRV\n              <jats:sup>R<\/jats:sup>\n            <\/jats:sub>\n            . The three novel compounds should be further developed as potential drugs for treating individuals harboring wild-type and multi-PI-resistant HIV variants as well as HIV\n            <jats:sub>\n              DRV\n              <jats:sup>R<\/jats:sup>\n            <\/jats:sub>\n            .\n          <\/jats:p>","DOI":"10.1128\/jvi.01829-15","type":"journal-article","created":{"date-parts":[[2015,11,19]],"date-time":"2015-11-19T03:34:17Z","timestamp":1447904057000},"page":"2180-2194","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["C-5-Modified Tetrahydropyrano-Tetrahydofuran-Derived Protease Inhibitors (PIs) Exert Potent Inhibition of the Replication of HIV-1 Variants Highly Resistant to Various PIs, including Darunavir"],"prefix":"10.1128","volume":"90","author":[{"given":"Manabu","family":"Aoki","sequence":"first","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy 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