{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:10:20Z","timestamp":1789135820160,"version":"build-2803163510"},"reference-count":66,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Doravirine (DOR) and islatravir (ISL) are inhibitors of human immunodeficiency virus type 1 (HIV-1) replication that block the viral reverse transcriptase (RT) by distinct mechanisms. The combination has demonstrated efficacy in Phase 3 clinical studies in both virologically suppressed and treatment-nai\u0308ve people living with HIV-1 and has the potential to mitigate the emergence of resistance-associated mutations through complementary virological profiles. RT bearing a single point mutation, F227C, is associated with resistance to DOR, yet is hypersusceptible to ISL. Here, we report cryoEM structures of islatravir triphosphate (ISL-TP) bound to wild-type (WT) RT and F227C RT. Comparison with the corresponding ISL-TP and dATP-bound WT RT structures reveals that the F227C mutation induces an unexpected conformational change in a loop of the palm domain that is positioned to gate substrate access, providing a structural basis for ISL hypersusceptibility.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00431","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:01:34Z","timestamp":1786114894000},"page":"3179-3190","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric Crosstalk\nbetween Inhibitor Binding Sites\nDrives Enhanced Islatravir Susceptibility in F227C HIV-1 Reverse\nTranscriptase"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9060-5673","authenticated-orcid":true,"given":"Corey W.","family":"Hecksel","sequence":"first","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0034-5362","authenticated-orcid":true,"given":"Susanne N.","family":"Walker","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6769-8816","authenticated-orcid":true,"given":"Izzat","family":"Raheem","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest","family":"Asante-Appiah","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3730-4676","authenticated-orcid":true,"given":"Guillermo","family":"Calero","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine , , , ,","place":["Pittsburgh, Pennsylvania, United States, 15213"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy L.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1205-5204","authenticated-orcid":true,"given":"Sandra B.","family":"Gabelli","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yacob","family":"Gomez-Llorente","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert P.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srivanya","family":"Tummala","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Vergara","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine , , , ,","place":["Pittsburgh, Pennsylvania, United States, 15213"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3533-3273","authenticated-orcid":true,"given":"Daniel J.","family":"Klein","sequence":"additional","affiliation":[{"name":"Merck & Co., Inc. , , , ,","place":["West Point, Pennsylvania, United States, 19486"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"issue":"1","key":"2026091109095245900_cit1","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev-virology-110615-035556","article-title":"The Discovery of Reverse Transcriptase","volume":"3","author":"Coffin","year":"2016","journal-title":"Annu.\nRev. Virol."},{"issue":"3","key":"2026091109095245900_cit2","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.jmb.2008.10.071","article-title":"Structure\nand Function of HIV-1 Reverse\nTranscriptase: Molecular Mechanisms of Polymerization and Inhibition","volume":"385","author":"Sarafianos","year":"2009","journal-title":"J. Mol. Biol."},{"issue":"6664","key":"2026091109095245900_cit3","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/34542","article-title":"A Mechanism\nfor All Polymerases","volume":"391","author":"Steitz","year":"1998","journal-title":"Nature"},{"issue":"13","key":"2026091109095245900_cit4","doi-asserted-by":"publisher","first-page":"6320","DOI":"10.1073\/pnas.90.13.6320","article-title":"Crystal Structure\nof Human Immunodeficiency Virus Type 1 Reverse Transcriptase Complexed\nwith Double-Stranded DNA at 3.0 A Resolution Shows Bent DNA","volume":"90","author":"Jacobo-Molina","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Biol."},{"issue":"9","key":"2026091109095245900_cit7","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.1002\/pro.3681","article-title":"Structural\nInsights into the Recognition of Nucleoside Reverse Transcriptase\nInhibitors by HIV-1 Reverse Transcriptase: First Crystal Structures\nwith Reverse Transcriptase and the Active Triphosphate Forms of Lamivudine\nand Emtricitabine","volume":"28","author":"Bertoletti","year":"2019","journal-title":"Protein Sci."},{"issue":"12","key":"2026091109095245900_cit8","doi-asserted-by":"publisher","first-page":"8125","DOI":"10.1093\/nar\/gku487","article-title":"Structures of HIV-1\nRT-RNA\/DNA Ternary Complexes with dATP and Nevirapine Reveal Conformational\nFlexibility of RNA\/DNA: Insights into Requirements for RNase H Cleavage","volume":"42","author":"Das","year":"2014","journal-title":"Nucleic Acids Res."},{"issue":"5394","key":"2026091109095245900_cit9","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1126\/science.282.5394.1669","article-title":"Structure of a Covalently\nTrapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications\nfor Drug Resistance","volume":"282","author":"Huang","year":"1998","journal-title":"Science"},{"issue":"2","key":"2026091109095245900_cit10","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1089\/oli.2008.0103","article-title":"Novel Aptamer Inhibitors\nof Human Immunodeficiency\nVirus Reverse Transcriptase","volume":"18","author":"Destefano","year":"2008","journal-title":"Oligonucleotides"},{"issue":"1","key":"2026091109095245900_cit11","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1002\/pro.2776","article-title":"Structure of HIV-1 Reverse Transcriptase Bound to a\nNovel 38-mer Hairpin Template-primer DNA Aptamer","volume":"25","author":"Miller","year":"2016","journal-title":"Protein Sci."},{"issue":"1","key":"2026091109095245900_cit12","doi-asserted-by":"publisher","first-page":"10553","DOI":"10.1038\/s41467-024-54618-y","article-title":"Structural Basis of\nDeoxynucleotide Addition by HIV-1 RT during Reverse Transcription","volume":"15","author":"Vergara","year":"2024","journal-title":"Nat. Commun."},{"key":"2026091109095245900_cit13","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.sbi.2020.07.005","article-title":"Advances\nin Understanding\nthe Initiation of HIV-1 Reverse Transcription","volume":"65","author":"Krupkin","year":"2020","journal-title":"Curr. Opin. Struct. Biol."},{"issue":"1","key":"2026091109095245900_cit14","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1038\/s41467-021-22628-9","article-title":"High-Resolution\nView of HIV-1 Reverse Transcriptase Initiation Complexes and Inhibition\nby NNRTI Drugs","volume":"12","author":"Ha","year":"2021","journal-title":"Nat. Commun."},{"key":"2026091109095245900_cit15","unstructured":"National Institute of Health HIV Info; FDA-Approved\nHIV Medicines. https:\/\/hivinfo.nih.gov\/understanding-hiv\/fact-sheets\/fda-approved-hiv-medicines. accessed 06 March 2026."},{"issue":"3","key":"2026091109095245900_cit16","doi-asserted-by":"publisher","first-page":"313","DOI":"10.2174\/092986706775476089","article-title":"HIV-1 Reverse Transcriptase: A Therapeutical\nTarget\nin the Spotlight","volume":"13","author":"Castro","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"2026091109095245900_cit17","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.sbi.2019.11.011","article-title":"Evolving Understanding\nof HIV-1 Reverse Transcriptase\nStructure, Function, Inhibition, and Resistance","volume":"61","author":"Ruiz","year":"2020","journal-title":"Curr. Opin. Struct. 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Biol."},{"issue":"1\u20132","key":"2026091109095245900_cit20","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.virusres.2008.01.002","article-title":"Mechanisms\nof Inhibition of HIV Replication by Non-Nucleoside\nReverse Transcriptase Inhibitors","volume":"134","author":"Sluis-Cremer","year":"2008","journal-title":"Virus Res."},{"issue":"10","key":"2026091109095245900_cit21","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1080\/17425255.2019.1673367","article-title":"Current and\nEmerging Non-Nucleoside\nReverse Transcriptase Inhibitors (NNRTIs) for HIV-1 Treatment","volume":"15","author":"Wang","year":"2019","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"issue":"8","key":"2026091109095245900_cit22","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1021\/jm960056x","article-title":"Complexes\nof HIV-1 Reverse Transcriptase with Inhibitors\nof the HEPT Series Reveal Conformational Changes Relevant to the Design\nof Potent Non-Nucleoside Inhibitors","volume":"39","author":"Hopkins","year":"1996","journal-title":"J. Med.\nChem."},{"key":"2026091109095245900_cit23","unstructured":"Panel\non Antiretroviral Guidelines for Adults and Adolescents. Guidelines\nfor the Use of Antiretroviral Agents in Adults and Adolescents With\nHIV. https:\/\/clinicalinfo.hiv.gov\/en\/guidelines\/hiv-clinical-guidelines-adult-and-adolescent-arv\/whats-new. accessed 06 March 2026."},{"issue":"3","key":"2026091109095245900_cit24","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1016\/S0960-894X(99)00010-4","article-title":"Nucleosides\nand Nucleotides. 183. Synthesis of 4\u2032 \u03b1-Branched Thymidines\nas a New Type of Antiviral Agent","volume":"9","author":"Sugimoto","year":"1999","journal-title":"Bioorg. Med.\nChem. Lett."},{"issue":"5","key":"2026091109095245900_cit25","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1128\/AAC.45.5.1539-1546.2001","article-title":"4\u2032-Ethynyl\nNucleoside Analogs: Potent Inhibitors of Multidrug-Resistant Human\nImmunodeficiency Virus Variants In Vitro","volume":"45","author":"Kodama","year":"2001","journal-title":"Antimicrob.\nAgents Chemother."},{"issue":"9","key":"2026091109095245900_cit26","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/d41573-019-00141-5","article-title":"Longer-lasting\nHIV drugs","volume":"18","author":"Mullard","year":"2019","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"51","key":"2026091109095245900_cit27","doi-asserted-by":"publisher","first-page":"35681","DOI":"10.1074\/jbc.M109.036616","article-title":"Mechanism\nof Inhibition of HIV-1 Reverse Transcriptase by 4\u2032-Ethynyl-2-Fluoro-2\u2032-Deoxyadenosine\nTriphosphate, a Translocation-Defective Reverse Transcriptase Inhibitor*","volume":"284","author":"Michailidis","year":"2009","journal-title":"J. Biol. Chem."},{"issue":"35","key":"2026091109095245900_cit28","doi-asserted-by":"publisher","first-page":"24533","DOI":"10.1074\/jbc.M114.562694","article-title":"4\u2032-Ethynyl-2-Fluoro-2\u2032-Deoxyadenosine\n(EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms*","volume":"289","author":"Michailidis","year":"2014","journal-title":"J. Biol. Chem."},{"issue":"33","key":"2026091109095245900_cit29","doi-asserted-by":"publisher","first-page":"9274","DOI":"10.1073\/pnas.1605223113","article-title":"Structural\nBasis of HIV Inhibition by Translocation-Defective\nRT Inhibitor 4\u2032-Ethynyl-2-Fluoro-2\u2032-Deoxyadenosine (EFdA)","volume":"113","author":"Salie","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"8","key":"2026091109095245900_cit30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3003308","article-title":"MK-8527 Is a Novel Inhibitor of HIV-1\nReverse Transcriptase Translocation with Potential for Extended-Duration\nDosing","volume":"23","author":"Raheem","year":"2025","journal-title":"PLoS Biol."},{"issue":"11","key":"2026091109095245900_cit31","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.1016\/j.biocel.2008.04.007","article-title":"2\u2032-Deoxy-4\u2032-C-Ethynyl-2-Halo-Adenosines\nActive against Drug-Resistant Human Immunodeficiency Virus Type 1\nVariants","volume":"40","author":"Kawamoto","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"issue":"3","key":"2026091109095245900_cit32","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1002\/jmv.2055","article-title":"Resistance\nProfile and Cross-resistance of HIV-1 among Patients Failing a Non-nucleoside\nReverse Transcriptase Inhibitor-containing Regimen*","volume":"65","author":"Delaugerre","year":"2001","journal-title":"J. Me\u0301d. Virol."},{"key":"2026091109095245900_cit33","unstructured":"Stanford University: hIV Drug Resistance Database; NNRTI Resistance Notes. https:\/\/hivdb.stanford.edu\/dr-summary\/resistance-notes\/NNRTI\/#f227l.c.i.v. accessed 06 February 2026."},{"issue":"10","key":"2026091109095245900_cit34","doi-asserted-by":"publisher","first-page":"4095","DOI":"10.3390\/v6104095","article-title":"Current Perspectives on HIV-1 Antiretroviral Drug Resistance","volume":"6","author":"Iyidogan","year":"2014","journal-title":"Viruses"},{"issue":"11","key":"2026091109095245900_cit35","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00224-19","article-title":"Two Coselected Distal\nMutations in HIV-1 Reverse Transcriptase\n(RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside\nAnalogs","volume":"93","author":"Boyer","year":"2019","journal-title":"J. Virol."},{"issue":"7","key":"2026091109095245900_cit36","doi-asserted-by":"publisher","first-page":"3248","DOI":"10.1128\/JVI.76.7.3248-3256.2002","article-title":"The M184V\nMutation\nReduces the Selective Excision of Zidovudine 5\u2032-Monophosphate\n(AZTMP) by the Reverse Transcriptase of Human Immunodeficiency Virus\nType 1","volume":"76","author":"Boyer","year":"2002","journal-title":"J. Virol."},{"issue":"2","key":"2026091109095245900_cit37","doi-asserted-by":"publisher","first-page":"372","DOI":"10.3390\/v2020372","article-title":"The Role of Nucleotide\nExcision by Reverse Transcriptase\nin HIV Drug Resistance","volume":"2","author":"Acosta-Hoyos","year":"2010","journal-title":"Viruses"},{"issue":"10","key":"2026091109095245900_cit38","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1038\/nsmb.1908","article-title":"Structural Basis of\nHIV-1 Resistance to AZT by Excision","volume":"17","author":"Tu","year":"2010","journal-title":"Nat. Struct.\nMol. Biol."},{"issue":"45","key":"2026091109095245900_cit39","doi-asserted-by":"publisher","first-page":"15908","DOI":"10.1021\/bi981200e","article-title":"Phenotypic\nMechanism of HIV-1 Resistance to 3\u2032-Azido-3\u2032-Deoxythymidine\n(AZT): Increased Polymerization Processivity and Enhanced Sensitivity\nto Pyrophosphate of the Mutant Viral Reverse Transcriptase \u2020","volume":"37","author":"Arion","year":"1998","journal-title":"Biochemistry"},{"issue":"6","key":"2026091109095245900_cit40","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00133-22","article-title":"Islatravir Has a\nHigh Barrier to Resistance and Exhibits a Differentiated Resistance\nProfile from Approved Nucleoside Reverse Transcriptase Inhibitors\n(NRTIs)","volume":"66","author":"Diamond","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"issue":"4","key":"2026091109095245900_cit41","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1093\/cid\/ciy540","article-title":"Doravirine\/Lamivudine\/Tenofovir\nDisoproxil Fumarate Is Non-Inferior to Efavirenz\/Emtricitabine\/Tenofovir\nDisoproxil Fumarate in Treatment-Naive Adults With Human Immunodeficiency\nVirus\u20131 Infection: Week 48 Results of the DRIVE-AHEAD Trial","volume":"68","author":"Orkin","year":"2019","journal-title":"Clin. Infect. Dis."},{"issue":"5","key":"2026091109095245900_cit42","doi-asserted-by":"publisher","DOI":"10.1016\/s2352-3018(18)30021-3","article-title":"Doravirine versus Ritonavir-Boosted Darunavir\nin Antiretroviral-Naive Adults with HIV-1 (DRIVE-FORWARD): 48-Week\nResults of a Randomised, Double-Blind, Phase 3, Non-Inferiority Trial","volume":"5","author":"Molina","year":"2018","journal-title":"Lancet HIV"},{"issue":"4","key":"2026091109095245900_cit43","doi-asserted-by":"publisher","first-page":"2241","DOI":"10.1128\/AAC.02650-15","article-title":"Doravirine\nSuppresses\nCommon Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants\nat Clinically Relevant Concentrations","volume":"60","author":"Feng","year":"2016","journal-title":"Antimicrob.\nAgents Chemother."},{"issue":"30","key":"2026091109095245900_cit44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203660119","article-title":"Cryo-EM Structures of\nWild-Type and E138K\/M184I Mutant HIV-1 RT\/DNA Complexed with Inhibitors\nDoravirine and Rilpivirine","volume":"119","author":"Singh","year":"2022","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"3","key":"2026091109095245900_cit45","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/j.bmcl.2013.12.070","article-title":"Discovery of MK-1439, an Orally Bioavailable Non-Nucleoside\nReverse Transcriptase Inhibitor Potent against a Wide Range of Resistant\nMutant HIV Viruses","volume":"24","author":"Co\u0302te\u0301","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"issue":"5","key":"2026091109095245900_cit46","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02223-21","article-title":"Doravirine\nand Islatravir Have Complementary Resistance Profiles and Create a\nCombination with a High Barrier to Resistance","volume":"66","author":"Lai","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"issue":"12","key":"2026091109095245900_cit47","doi-asserted-by":"publisher","first-page":"169100","DOI":"10.1016\/j.jmb.2025.169100","article-title":"Kinetic Investigation\nof Resistance to Islatravir Conferred by Mutations in HIV-1 Reverse\nTranscriptase","volume":"437","author":"Zalenski","year":"2025","journal-title":"J. Mol. 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