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Integrase strand transfer inhibitors (INSTIs) are frontline treatments used in combination antiretroviral therapy, but their efficacy can be compromised by emergence of resistance-associated mutations. The development of compounds that will retain efficacy against drug-resistant variants is of significant interest. Herein, we report the synthesis of naphthyridine-based INSTIs with a combination of 4-amino and 5-hydroxymethyl groups. Comparison of the resistance mutant profiles of the new compounds with FDA-approved second-generation INSTIs showed that the lead compounds are comparable to or surpass the efficacy of clinically used drugs against some of the most prevalent drug-resistant mutations that emerge in patient-derived viral isolates. High-resolution cryogenic electron microscopy (cryo-EM) structures of HIV-1 intasomes with two of the best naphthyridine-based INSTIs bound highlight how these inhibitors make enhanced interactions with viral DNA, particularly through optimized DNA stacking. Molecular dynamics simulations together with quantum mechanical and molecular mechanical calculations indicate that the interplay between intramolecular bonding, stacking geometry, resonance effects, and charge distribution governs drug binding within the active site of the intasome. The data mechanistically explain how key interactions contribute to improved antiviral potency against drug-resistant mutants and highlight a new strategy to combat HIV-1 resistance.<\/jats:p>","DOI":"10.1093\/narmme\/ugaf039","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T13:15:36Z","timestamp":1763558136000},"source":"Crossref","is-referenced-by-count":2,"title":["Pi\u2013pi stacking interactions with viral DNA contribute to the potency of naphthyridine-based HIV-1 integrase inhibitors"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1006-6364","authenticated-orcid":false,"given":"Xue Zhi","family":"Zhao","sequence":"first","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, MD 21702 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J","family":"Smith","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, MD 21702 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvin","family":"Karbasi","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, MD 21702 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indrani","family":"Choudhuri","sequence":"additional","affiliation":[{"name":"The Salk Institute for Biological Studies , La Jolla, CA 92037 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jing","sequence":"additional","affiliation":[{"name":"The Salk Institute for Biological Studies , La Jolla, CA 92037 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8124-7472","authenticated-orcid":false,"given":"Dmitry","family":"Lyumkis","sequence":"additional","affiliation":[{"name":"The Salk Institute for Biological Studies , La Jolla, CA 92037 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Craigie","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD 20892 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Terrence R","family":"Burke","sequence":"additional","affiliation":[{"name":"Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Frederick, MD 21702 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"2025121901272584900_B1","doi-asserted-by":"publisher","first-page":"12730","DOI":"10.1021\/acs.chemrev.6b00125","article-title":"Retroviral DNA integration","volume":"116","author":"Lesbats","year":"2016","journal-title":"Chem Rev"},{"key":"2025121901272584900_B2","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1021\/acschembio.5b00948","article-title":"HIV-1 integrase strand transfer inhibitors with reduced susceptibility to drug resistant mutant 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