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As successful management of the disease requires lifelong treatment, the emergence of resistance mutations is inevitable, making development of new RT inhibitors, which remain effective against resistant variants crucial. To this end, previous computationally guided drug design efforts have resulted in catechol diether compounds, which inhibit wildtype RT with picomolar affinities and appear to be promising preclinical candidates. To confirm that these compounds remain potent against Y181C, a widespread mutation conferring resistance to first generation inhibitors, they were screened against the HIV\u20101 N119 clinical isolate, reported as a Y181C single mutant. In comparison to a molecular clone with the same mutation, N119 appears less susceptible to inhibition by our preclinical candidate compounds. A more detailed sequencing effort determined that N119 was misidentified and carries V106A in combination with Y181C. While both indolizine and naphthalene substituted catechol diethers are potent against the classical Y181C single mutant, the addition of V106A confers more resistance against the indolizine derivatives than the naphthalene derivatives. Crystal structures presented in this study highlight key features of the naphthyl group, which allow these compounds to remain potent in the double mutant, including stronger interactions with F227 and less reliance on V106 for stabilization of the ethoxy\u2010uracil ring, which makes critical hydrogen bonds with other residues in the binding pocket.<\/jats:p>","DOI":"10.1002\/pro.4814","type":"journal-article","created":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T14:29:55Z","timestamp":1697812195000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring novel <scp>HIV<\/scp>\u20101 reverse transcriptase inhibitors with drug\u2010resistant mutants: A double mutant surprise"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-6557","authenticated-orcid":false,"given":"Klarissa","family":"Hollander","sequence":"first","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Pharmacology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-8483","authenticated-orcid":false,"given":"Albert H.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7419-8633","authenticated-orcid":false,"given":"Kathleen M.","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Hunker","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph A.","family":"Ippolito","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Chemistry Yale University  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krasimir A.","family":"Spasov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang\u2010Hui J.","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3993-9520","authenticated-orcid":false,"given":"William L.","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"Department of Chemistry Yale University  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7046-0147","authenticated-orcid":false,"given":"Ya\u2010Chi","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3433-0780","authenticated-orcid":false,"given":"Karen S.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Molecular Biophysics and Biochemistry Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Pharmacology Yale 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