{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:25:42Z","timestamp":1790713542040,"version":"4.1.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T00:00:00Z","timestamp":1626912000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI141327"],"award-info":[{"award-number":["AI141327"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research contract, ST Pharm, Ltd"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI143649"],"award-info":[{"award-number":["AI143649"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI039394"],"award-info":[{"award-number":["AI039394"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Allosteric integrase inhibitors (ALLINIs) are a class of experimental anti-HIV agents that target the noncatalytic sites of the viral integrase (IN) and interfere with the IN-viral RNA interaction during viral maturation. Here, we report a highly potent and safe pyrrolopyridine-based ALLINI, STP0404, displaying picomolar IC\n                    <jats:sub>50<\/jats:sub>\n                    in human PBMCs with a &gt;24,000 therapeutic index against HIV-1. X-ray structural and biochemical analyses revealed that STP0404 binds to the host LEDGF\/p75 protein binding pocket of the IN dimer, which induces aberrant IN oligomerization and blocks the IN-RNA interaction. Consequently, STP0404 inhibits proper localization of HIV-1 RNA genomes in viral particles during viral maturation. Y99H and A128T mutations at the LEDGF\/p75 binding pocket render resistance to STP0404. Extensive\n                    <jats:italic>in vivo<\/jats:italic>\n                    pharmacological and toxicity investigations demonstrate that STP0404 harbors outstanding therapeutic and safety properties. Overall, STP0404 is a potent and first-in-class ALLINI that targets LEDGF\/p75 binding site and has advanced to a human trial.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009671","type":"journal-article","created":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T13:25:22Z","timestamp":1626960322000},"page":"e1009671","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF\/p75-integrase interaction site"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9639-2250","authenticated-orcid":true,"given":"Tatsuya","family":"Maehigashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4899-975X","authenticated-orcid":true,"given":"Seohyun","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uk-Il","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jared","family":"Lindenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2469-5391","authenticated-orcid":true,"given":"Adrian","family":"Oo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratibha C.","family":"Koneru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijan","family":"Mahboubi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9709-2591","authenticated-orcid":true,"given":"Alan N.","family":"Engelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamuka","family":"Kvaratskhelia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8271-7640","authenticated-orcid":true,"given":"Kyungjin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7986-4335","authenticated-orcid":true,"given":"Baek","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,7,22]]},"reference":[{"issue":"2","key":"ppat.1009671.ref001","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.sbi.2010.12.005","article-title":"Structural insights into the retroviral DNA integration apparatus","volume":"21","author":"P Cherepanov","year":"2011","journal-title":"Curr Opin Struct Biol"},{"issue":"4","key":"ppat.1009671.ref002","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/nrmicro2747","article-title":"The structural biology of HIV-1: mechanistic and therapeutic insights","volume":"10","author":"A Engelman","year":"2012","journal-title":"Nat Rev Microbiol"},{"issue":"5453","key":"ppat.1009671.ref003","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1126\/science.287.5453.646","article-title":"Inhibitors of strand transfer that prevent integration and inhibit HIV- 1 replication in cells","volume":"287","author":"DJ Hazuda","year":"2000","journal-title":"Science"},{"issue":"1","key":"ppat.1009671.ref004","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.antiviral.2009.11.004","article-title":"Strand transfer inhibitors of HIV-1 integrase: bringing IN a new era of antiretroviral therapy","volume":"85","author":"DJ McColl","year":"2010","journal-title":"Antiviral Res"},{"issue":"5","key":"ppat.1009671.ref005","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1097\/COH.0b013e3283567309","article-title":"HIV integrase as a target for antiretroviral therapy","volume":"7","author":"DJ Hazuda","year":"2012","journal-title":"Curr Opin HIV AIDS"},{"issue":"7286","key":"ppat.1009671.ref006","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nature08784","article-title":"Retroviral intasome assembly and inhibition of DNA strand transfer","volume":"464","author":"S Hare","year":"2010","journal-title":"Nature"},{"issue":"1","key":"ppat.1009671.ref007","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1074\/jbc.M209278200","article-title":"HIV-1 integrase forms stable tetramers and associates with LEDGF\/p75 protein in human cells","volume":"278","author":"P Cherepanov","year":"2003","journal-title":"J Biol Chem"},{"issue":"12","key":"ppat.1009671.ref008","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1038\/nm1329","article-title":"A role for LEDGF\/p75 in targeting HIV DNA integration","volume":"11","author":"A Ciuffi","year":"2005","journal-title":"Nat Med"},{"issue":"5798","key":"ppat.1009671.ref009","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1126\/science.1132319","article-title":"An essential role for LEDGF\/p75 in HIV integration","volume":"314","author":"M Llano","year":"2006","journal-title":"Science"},{"issue":"14","key":"ppat.1009671.ref010","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1101\/gad.1565107","article-title":"LEDGF\/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration","volume":"21","author":"MC Shun","year":"2007","journal-title":"Genes Dev"},{"issue":"18","key":"ppat.1009671.ref011","doi-asserted-by":"crossref","first-page":"17841","DOI":"10.1074\/jbc.M411681200","article-title":"The interaction of LEDGF\/p75 with integrase is lentivirus-specific and promotes DNA binding","volume":"280","author":"K Busschots","year":"2005","journal-title":"J Biol Chem"},{"issue":"48","key":"ppat.1009671.ref012","doi-asserted-by":"crossref","first-page":"17308","DOI":"10.1073\/pnas.0506924102","article-title":"Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75","volume":"102","author":"P Cherepanov","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"ppat.1009671.ref013","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/nchembio.370","article-title":"Rational design of small-molecule inhibitors of the LEDGF\/p75-integrase interaction and HIV replication","volume":"6","author":"F Christ","year":"2010","journal-title":"Nat Chem Biol"},{"issue":"5","key":"ppat.1009671.ref014","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.cell.2016.07.044","article-title":"HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis","volume":"166","author":"JJ Kessl","year":"2016","journal-title":"Cell"},{"issue":"30","key":"ppat.1009671.ref015","doi-asserted-by":"crossref","first-page":"20477","DOI":"10.1074\/jbc.M114.551119","article-title":"Allosteric Inhibition of Human Immunodeficiency Virus Integrase: LATE BLOCK DURING VIRAL REPLICATION AND ABNORMAL MULTIMERIZATION INVOLVING SPECIFIC PROTEIN DOMAINS","volume":"289","author":"K Gupta","year":"2014","journal-title":"J Biol Chem"},{"issue":"7","key":"ppat.1009671.ref016","doi-asserted-by":"crossref","first-page":"e103552","DOI":"10.1371\/journal.pone.0103552","article-title":"The allosteric HIV-1 integrase inhibitor BI-D affects virion maturation but does not influence packaging of a functional RNA genome","volume":"9","author":"N van Bel","year":"2014","journal-title":"PLoS One"},{"issue":"9","key":"ppat.1009671.ref017","doi-asserted-by":"crossref","first-page":"e74163","DOI":"10.1371\/journal.pone.0074163","article-title":"Non-Catalytic Site HIV-1 Integrase Inhibitors Disrupt Core Maturation and Induce a Reverse Transcription Block in Target Cells","volume":"8","author":"M Balakrishnan","year":"2013","journal-title":"PLoS One"},{"key":"ppat.1009671.ref018","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1742-4690-10-57","article-title":"LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions.","volume":"10","author":"BA Desimmie","year":"2013","journal-title":"Retrovirology"},{"issue":"19","key":"ppat.1009671.ref019","doi-asserted-by":"crossref","first-page":"9765","DOI":"10.1128\/JVI.01522-15","article-title":"Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation","volume":"89","author":"J Fontana","year":"2015","journal-title":"J Virol"},{"issue":"21","key":"ppat.1009671.ref020","doi-asserted-by":"crossref","first-page":"8690","DOI":"10.1073\/pnas.1300703110","article-title":"Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation","volume":"110","author":"KA Jurado","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"25","key":"ppat.1009671.ref021","doi-asserted-by":"crossref","first-page":"21189","DOI":"10.1074\/jbc.M112.347534","article-title":"New class of HIV-1 integrase (IN) inhibitors with a dual mode of action","volume":"287","author":"M Tsiang","year":"2012","journal-title":"J Biol Chem"},{"key":"ppat.1009671.ref022","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/1742-4690-10-144","article-title":"Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage","volume":"10","author":"E Le Rouzic","year":"2013","journal-title":"Retrovirology"},{"issue":"5","key":"ppat.1009671.ref023","doi-asserted-by":"crossref","first-page":"e1004171","DOI":"10.1371\/journal.ppat.1004171","article-title":"new class of multimerization selective inhibitors of HIV-1 integrase","volume":"10","author":"A Sharma","year":"2014","journal-title":"PLoS Pathog."},{"issue":"4","key":"ppat.1009671.ref024","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1021\/ml500002n","article-title":"Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1","volume":"5","author":"LD Fader","year":"2014","journal-title":"ACS Med Chem Lett"},{"issue":"19","key":"ppat.1009671.ref025","doi-asserted-by":"crossref","first-page":"4748","DOI":"10.1016\/j.bmcl.2016.08.037","article-title":"Indole-based allosteric inhibitors of HIV-1 integrase","volume":"26","author":"PA Patel","year":"2016","journal-title":"Bioorg Med Chem Lett"},{"issue":"16","key":"ppat.1009671.ref026","doi-asserted-by":"crossref","first-page":"6172","DOI":"10.1074\/jbc.M117.816793","article-title":"Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration","volume":"293","author":"D Bonnard","year":"2018","journal-title":"J Biol Chem"},{"key":"ppat.1009671.ref027","unstructured":"Mitchell M, Balakrishnan M, Brizgys G, Cai R, Lansdon E, Mulato A, et al., editors. Novel non-catalytic site integrase inhibitor with improved resistance profile. Conference on Retroviruses and Opportunistic Infections (CROI); 2017."},{"key":"ppat.1009671.ref028","unstructured":"Mitchell ML, Roethle PA, Xu L, Yang H, Mcfadden R, Babaoglu K. Benzothiazole compounds and their pharmaceutical use. Google Patents; 2015."},{"issue":"1","key":"ppat.1009671.ref029","first-page":"1","article-title":"Natural variation of HIV-1 group M integrase: implications for a new class of antiretroviral inhibitors","volume":"5","author":"S-Y Rhee","year":"2008"},{"issue":"12","key":"ppat.1009671.ref030","doi-asserted-by":"crossref","first-page":"e1002584","DOI":"10.1371\/journal.pbio.1002584","article-title":"Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase","volume":"14","author":"K Gupta","year":"2016","journal-title":"PLoS Biol"},{"key":"ppat.1009671.ref031","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.46344","article-title":"HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors","volume":"8","author":"PC Koneru","year":"2019","journal-title":"eLife"},{"issue":"45","key":"ppat.1009671.ref032","doi-asserted-by":"crossref","first-page":"23569","DOI":"10.1074\/jbc.M116.753384","article-title":"A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain","volume":"291","author":"D Patel","year":"2016","journal-title":"J Biol Chem"},{"key":"ppat.1009671.ref033","doi-asserted-by":"crossref","first-page":"16801","DOI":"10.1074\/jbc.M112.354373","article-title":"A multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors","volume":"287","author":"JJ Kessl","year":"2012","journal-title":"J Biol Chem"},{"issue":"22","key":"ppat.1009671.ref034","doi-asserted-by":"crossref","first-page":"15813","DOI":"10.1074\/jbc.M112.443390","article-title":"The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors","volume":"288","author":"L Feng","year":"2013","journal-title":"J Biol Chem"},{"issue":"6","key":"ppat.1009671.ref035","first-page":"3233","volume":"58","author":"C Fenwick","year":"2014","journal-title":"Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor"},{"key":"ppat.1009671.ref036","article-title":"ICH guideline S6 (R1)\u2013preclinical safety evaluation of biotechnology-derived","author":"Agency CfMPfHUJEM","year":"2011","journal-title":"pharmaceuticals"},{"issue":"Pt 8","key":"ppat.1009671.ref037","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1107\/S0907444906019949","article-title":"HKL-3000: the integration of data reduction and structure solution\u2014from diffraction images to an initial model in minutes","volume":"62","author":"W Minor","year":"2006","journal-title":"Acta Crystallogr D"},{"key":"ppat.1009671.ref038","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing of X-ray diffraction data collected in oscillation mode","volume":"276","author":"Z Otwinowski","year":"1997","journal-title":"Methods Enzymol"},{"issue":"Pt 4","key":"ppat.1009671.ref039","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1107\/S0021889807021206","article-title":"Phaser crystallographic software","volume":"40","author":"AJ McCoy","year":"2007","journal-title":"J Appl Crystallogr"},{"issue":"Pt 2","key":"ppat.1009671.ref040","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX: a comprehensive Python-based system for macromolecular structure solution","volume":"66","author":"PD Adams","year":"2010","journal-title":"Acta Crystallogr D"},{"issue":"Pt 4","key":"ppat.1009671.ref041","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1107\/S0907444912001308","article-title":"Towards automated crystallographic structure refinement with phenix.refine","volume":"68","author":"PV Afonine","year":"2012","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"issue":"Pt 4","key":"ppat.1009671.ref042","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and development of Coot","volume":"66","author":"P Emsley","year":"2010","journal-title":"Acta Crystallogr D"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009671","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,22]],"date-time":"2021-07-22T13:25:53Z","timestamp":1626960353000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009671"}},"subtitle":[],"editor":[{"given":"Bryan R.","family":"Cullen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,7,22]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1009671","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,22]]}}}