{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T20:52:33Z","timestamp":1788555153038,"version":"build-2803163510"},"reference-count":45,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Non\u2010nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit reverse transcription and block the replication of HIV\u20101. Currently, NNRTIs are usually used as part of a three\u2010drug combination given to patients as antiretroviral therapy. These combinations involve other classes of anti\u2010HIV\u20101 drugs, commonly nucleoside reverse transcriptase inhibitors (NRTIs). However, attempts are being made to develop two\u2010drug maintenance therapies, some of which involve an NNRTI and an integrase strand transfer inhibitor. This has led to a renewed interest in developing novel NNRTIs, with a major emphasis on designing compounds that can effectively inhibit the known NNRTI\u2010resistant mutants. We have generated and tested novel rilpivirine (RPV) analogs. The new compounds were designed to exploit a small opening in the upper right periphery of the NNRTI\u2010binding pocket. The best of the new compounds, <jats:bold>12<\/jats:bold>, was a more potent inhibitor of the NNRTI\u2010resistant mutants we tested than either doravirine or efavirenz but was inferior to RPV. We describe the limitations on the modifications that can be appended to the \u201cupper right side\u201d of the RPV core and the effects of substituting other cores for the central pyrimidine core of RPV and make suggestions about how this information can be used in NNRTI design.<\/jats:p>","DOI":"10.1111\/cbdd.13766","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T02:39:45Z","timestamp":1596422385000},"page":"4-17","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structure\u2010based non\u2010nucleoside inhibitor design: Developing inhibitors that are effective against resistant mutants"],"prefix":"10.1111","volume":"97","author":[{"given":"Steven J.","family":"Smith","sequence":"first","affiliation":[{"name":"HIV Dynamics and Replication Program Center for Cancer Research National Cancer Institute Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary T.","family":"Pauly","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory Center for Cancer Research National Cancer Institute Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine","family":"Hewlett","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program Center for Cancer Research National Cancer Institute Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel P.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory Center for Cancer Research National Cancer Institute Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9176-4377","authenticated-orcid":false,"given":"Stephen H.","family":"Hughes","sequence":"additional","affiliation":[{"name":"HIV Dynamics and Replication Program Center for Cancer Research National Cancer Institute Frederick MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-017-0820-3"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32462-0"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2018.1478726"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.359.6381.1205"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2013.03.012"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2013.03.014"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0711209105"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2004.07.001"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.2223"},{"key":"e_1_2_8_11_1","first-page":"215","article-title":"Dolutegravir\/rilpivirine for the treatment of HIV\u20101 infection","volume":"10","author":"Dowers E.","year":"2018","journal-title":"HIV AIDS (Auckl)"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04201-14"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3851\/IMP1803"},{"key":"e_1_2_8_14_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3389\/fmicb.2019.00369","article-title":"A 28\u2010year history of HIV\u20101 drug resistance and transmission in Washington, DC","volume":"10","author":"Gibson K. M.","year":"2019","journal-title":"Frontiers in Microbiology"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2018.09.013"},{"issue":"4","key":"e_1_2_8_16_1","first-page":"127","article-title":"Investigational antiretroviral drugs: What is coming down the pipeline","volume":"25","author":"Gulick R. M.","year":"2018","journal-title":"Topics in Antiviral Medicine"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-041217-013717"},{"issue":"5","key":"e_1_2_8_18_1","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1093\/infdis\/172.5.1379","article-title":"A pilot study to evaluate the development of resistance to nevirapine in asymptomatic human immunodeficiency virus\u2010infected patients with CD4 cell counts of >500\/mm3: AIDS Clinical Trials Group Protocol 208","volume":"172","author":"Havlir D.","year":"1995","journal-title":"Journal of Infectious Diseases"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01729"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-9-99"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.13429"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01656"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01827"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)33095-7"},{"issue":"4","key":"e_1_2_8_25_1","doi-asserted-by":"crossref","first-page":"e46","DOI":"10.1371\/journal.ppat.0030046","article-title":"ART suppresses plasma HIV\u20101 RNA to a stable set point predicted by pretherapy viremia","volume":"3","author":"Maldarelli F.","year":"2007","journal-title":"PLoS Path"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13181-013-0325-8"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00152-8"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31917-7"},{"issue":"4","key":"e_1_2_8_29_1","doi-asserted-by":"crossref","first-page":"19980","DOI":"10.7448\/IAS.18.4.19980","article-title":"Antiretroviral pre\u2010exposure prophylaxis implementation in the United States: A work in progress","volume":"18","author":"Mayer K. H.","year":"2015","journal-title":"Journal of the International AIDS Society"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00056-2"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00843"},{"issue":"1","key":"e_1_2_8_32_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/s12879-019-3817-6","article-title":"Effectiveness and safety of dual therapy with rilpivirine and boosted darunavir in treatment\u2010experienced patients with advanced HIV infection: A preliminary 24 week analysis (RIDAR study)","volume":"19","author":"Pasquau J.","year":"2019","journal-title":"BMC Infectious Diseases"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/387188a0"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222366699"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/op8000383"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200060060-00013"},{"issue":"24","key":"e_1_2_8_37_1","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.1056\/NEJMoa030265","article-title":"Comparison of four\u2010drug regimens and pairs of sequential three\u2010drug regimens as initial therapy for HIV\u20101 infection","volume":"349","author":"Shafer R. W.","year":"2003","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virusres.2008.01.002"},{"issue":"51400","key":"e_1_2_8_39_1","article-title":"Rapid screening of HIV reverse transcriptase and integrase inhibitors","volume":"86","author":"Smith S. J.","year":"2014","journal-title":"Journal of Visualized Experiments"},{"issue":"5","key":"e_1_2_8_40_1","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1097\/QAI.0000000000001031","article-title":"Rilpivirine and doravirine have complementary efficacies against NNRTI\u2010resistant HIV\u20101 Mutants","volume":"72","author":"Smith S. J.","year":"2016","journal-title":"Journal of Acquired Immune Deficiency Syndromes"},{"key":"e_1_2_8_41_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12977-016-0244-2","article-title":"Rilpivirine analogs potently inhibit drug\u2010resistant HIV\u20101 mutants","volume":"13","author":"Smith S. J.","year":"2016","journal-title":"Retrovirology"},{"issue":"9","key":"e_1_2_8_42_1","doi-asserted-by":"crossref","first-page":"e01035\u201318","DOI":"10.1128\/AAC.01035-18","article-title":"HIV\u20101 integrase inhibitors that are broadly effective against drug\u2010resistant mutants","volume":"62","author":"Smith S. J.","year":"2018","journal-title":"Antimicrobial Agents and Chemotherapy"},{"issue":"19","key":"e_1_2_8_43_1","doi-asserted-by":"crossref","first-page":"9817","DOI":"10.1128\/JVI.00991-10","article-title":"Divergent evolution in reverse transcriptase (RT) of HIV\u20101 group O and M lineages: Impact on structure, fitness, and sensitivity to nonnucleoside RT inhibitors","volume":"84","author":"Tebit D. M.","year":"2010","journal-title":"Journal of Virology"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2019.1673367"},{"issue":"3","key":"e_1_2_8_45_1","first-page":"111","article-title":"2019 update of the drug resistance mutations in HIV\u20101","volume":"27","author":"Wensing A. M.","year":"2019","journal-title":"Topics in Antiviral Medicine"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2019.11.011"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcbdd.13766","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.13766","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cbdd.13766","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.13766","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T13:47:55Z","timestamp":1693748875000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.13766"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,17]]},"references-count":45,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1111\/cbdd.13766"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.13766","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"value":"1747-0277","type":"print"},{"value":"1747-0285","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,17]]},"assertion":[{"value":"2020-04-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-09-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}