{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:06:18Z","timestamp":1790802378867,"version":"4.1.0"},"reference-count":36,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"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":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            In the present study, GRL008, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), and darunavir (DRV), both of which contain a P2-\n            <jats:italic>bis<\/jats:italic>\n            -tetrahydrofuranyl urethane (\n            <jats:italic>bis<\/jats:italic>\n            -THF) moiety, were found to exert potent antiviral activity (50% effective concentrations [EC\n            <jats:sub>50<\/jats:sub>\n            s], 0.029 and 0.002 \u03bcM, respectively) against a multidrug-resistant clinical isolate of HIV-1 (HIV\n            <jats:sub>A02<\/jats:sub>\n            ) compared to ritonavir (RTV; EC\n            <jats:sub>50<\/jats:sub>\n            , &gt;1.0 \u03bcM) and tipranavir (TPV; EC\n            <jats:sub>50<\/jats:sub>\n            , 0.364 \u03bcM). Additionally, GRL008 showed potent antiviral activity against an HIV-1 variant selected in the presence of DRV over 20 passages (HIV\n            <jats:sub>DRV<\/jats:sub>\n            <jats:sup>R<\/jats:sup>\n            <jats:sub>P20<\/jats:sub>\n            ), with a 2.6-fold increase in its EC\n            <jats:sub>50<\/jats:sub>\n            (0.097 \u03bcM) compared to its corresponding EC\n            <jats:sub>50<\/jats:sub>\n            (0.038 \u03bcM) against wild-type HIV-1\n            <jats:sub>NL4-3<\/jats:sub>\n            (HIV\n            <jats:sub>WT<\/jats:sub>\n            ). Based on X-ray crystallographic analysis, both GRL008 and DRV showed strong hydrogen bonds (H-bonds) with the backbone-amide nitrogen\/carbonyl oxygen atoms of conserved active-site amino acids G27, D29, D30, and D30\u2032 of HIV\n            <jats:sub>A02<\/jats:sub>\n            protease (PR\n            <jats:sub>A02<\/jats:sub>\n            ) and wild-type PR in their corresponding crystal structures, while TPV lacked H-bonds with G27 and D30\u2032 due to an absence of polar groups. The P2\u2032 thiazolyl moiety of RTV showed two conformations in the crystal structure of the PR\n            <jats:sub>A02<\/jats:sub>\n            -RTV complex, one of which showed loss of contacts in the S2\u2032 binding pocket of PR\n            <jats:sub>A02<\/jats:sub>\n            , supporting RTV's compromised antiviral activity (EC\n            <jats:sub>50<\/jats:sub>\n            , &gt;1 \u03bcM). Thus, the conserved H-bonding network of P2-\n            <jats:italic>bis<\/jats:italic>\n            -THF-containing GRL008 with the backbone of G27, D29, D30, and D30\u2032 most likely contributes to its persistently greater antiviral activity against HIV\n            <jats:sub>WT<\/jats:sub>\n            , HIV\n            <jats:sub>A02<\/jats:sub>\n            , and HIV\n            <jats:sub>DRV<\/jats:sub>\n            <jats:sup>R<\/jats:sup>\n            <jats:sub>P20<\/jats:sub>\n            .\n          <\/jats:p>","DOI":"10.1128\/aac.00107-14","type":"journal-article","created":{"date-parts":[[2014,4,22]],"date-time":"2014-04-22T03:52:32Z","timestamp":1398138752000},"page":"3679-3688","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["A Conserved Hydrogen-Bonding Network of P2\n            <i>bis<\/i>\n            -Tetrahydrofuran-Containing HIV-1 Protease Inhibitors (PIs) with a Protease Active-Site Amino Acid Backbone Aids in Their Activity against PI-Resistant HIV"],"prefix":"10.1128","volume":"58","author":[{"given":"Ravikiran S.","family":"Yedidi","sequence":"first","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harisha","family":"Garimella","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Aoki","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto, Japan"},{"name":"Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Aoki-Ogata","sequence":"additional","affiliation":[{"name":"Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darshan V.","family":"Desai","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Davis","sequence":"additional","affiliation":[{"name":"Retroviral Disease Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. Sean","family":"Fyvie","sequence":"additional","affiliation":[{"name":"Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Smith","sequence":"additional","affiliation":[{"name":"Life Sciences Collaborative Access Team, Synchrotron Research Center, Northwestern University, Argonne, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debananda","family":"Das","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul T.","family":"Wingfield","sequence":"additional","affiliation":[{"name":"Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Maeda","sequence":"additional","affiliation":[{"name":"Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun K.","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana, 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