{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T07:18:01Z","timestamp":1718867881224},"reference-count":39,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"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":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5-dimethylbenzyl)-5-iodopyrimidine-2,4(1\n            <jats:italic>H<\/jats:italic>\n            ,3\n            <jats:italic>H<\/jats:italic>\n            )-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC\n            <jats:sub>50<\/jats:sub>\n            ) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC\n            <jats:sub>50<\/jats:sub>\n            of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of &gt;1 \u00d7 10\n            <jats:sup>4<\/jats:sup>\n            . A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC\n            <jats:sub>50<\/jats:sub>\n            s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants,\n            <jats:italic>in vitro<\/jats:italic>\n            resistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, these\n            <jats:italic>in vitro<\/jats:italic>\n            data indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted.\n          <\/jats:p>","DOI":"10.1128\/aac.00440-15","type":"journal-article","created":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T19:10:15Z","timestamp":1433963415000},"page":"4882-4888","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes"],"prefix":"10.1128","volume":"59","author":[{"given":"Weisi","family":"Xu","sequence":"first","affiliation":[{"name":"State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS\/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxiong","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Peking University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianping","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing You'an Hospital, Capital Medical University, Beijing, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Yin","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS\/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS\/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Jiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS\/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyi","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Peking University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shibo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, USA"},{"name":"Key Laboratory of Medical Molecular Virology of MOE\/MOH and Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiming","family":"Shao","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS\/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowei","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Peking University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liying","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Center for AIDS\/STD Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113031"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12403"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1302976"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nature13647","article-title":"HIV: early treatment may not be early enough","volume":"512","author":"Deng K","year":"2014","unstructured":"Deng K, Siliciano RF. 2014. 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