{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:57:03Z","timestamp":1790783823275,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009060","name":"Sidaction","doi-asserted-by":"publisher","award":["AO 29 -12026"],"award-info":[{"award-number":["AO 29 -12026"]}],"id":[{"id":"10.13039\/100009060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Multiple viral targets are now available in the clinic to fight HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients due to resistance, with or without treatment-adherence glitches. Accordingly, it is important to better understand how HIV and other retroviruses replicate in order to propose alternative antiviral strategies. Recent studies have shown that multiple cellular factors are implicated during the integration step and, more specifically, that integrase can be regulated through post-translational modifications. We have shown that integrase is phosphorylated by GCN2, a cellular protein kinase of the integrated stress response, leading to a restriction of HIV replication. In addition, we found that this mechanism is conserved among other retroviruses. Accordingly, we developed an in vitro interaction assay, based on the AlphaLISA technology, to monitor the integrase-GCN2 interaction. From an initial library of 133 FDA-approved molecules, we identified nine compounds that either inhibited or stimulated the interaction between GCN2 and HIV integrase. In vitro characterization of these nine hits validated this pilot screen and demonstrated that the GCN2-integrase interaction could be a viable solution for targeting integrase out of its active site.<\/jats:p>","DOI":"10.3390\/molecules26175423","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T21:47:38Z","timestamp":1630964858000},"page":"5423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Targeting the Integrated Stress Response Kinase GCN2 to Modulate Retroviral Integration"],"prefix":"10.3390","volume":"26","author":[{"given":"Chlo\u00e9","family":"Torres","sequence":"first","affiliation":[{"name":"Univ. Bordeaux, CNRS, UMR 5234, Microbiologie Fondamentale et Pathog\u00e9nicit\u00e9, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asja","family":"Garling","sequence":"additional","affiliation":[{"name":"Univ. Bordeaux, CNRS, UMR 5234, Microbiologie Fondamentale et Pathog\u00e9nicit\u00e9, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u00efd","family":"Taouji","sequence":"additional","affiliation":[{"name":"Actions for onCogenesis Understanding and Target Identification in ONcology (ACTION), UMR 1218, Bergonie Institute, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Calmels","sequence":"additional","affiliation":[{"name":"Univ. Bordeaux, CNRS, UMR 5234, Microbiologie Fondamentale et Pathog\u00e9nicit\u00e9, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9808-7391","authenticated-orcid":false,"given":"Marie-Line","family":"Andreola","sequence":"additional","affiliation":[{"name":"Univ. Bordeaux, CNRS, UMR 5234, Microbiologie Fondamentale et Pathog\u00e9nicit\u00e9, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8103-9120","authenticated-orcid":false,"given":"Mathieu","family":"M\u00e9tifiot","sequence":"additional","affiliation":[{"name":"Univ. Bordeaux, CNRS, UMR 5234, Microbiologie Fondamentale et Pathog\u00e9nicit\u00e9, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gupta, P.K., and Saxena, A. (2021). HIV\/AIDS: Current Updates on the Disease, Treatment and Prevention. Proc. Natl. Acad. Sci. India Sect. B Biol. Sci., 1\u201316.","DOI":"10.1007\/s40011-021-01237-y"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.3201\/eid2706.210284","article-title":"Reflections on 40 Years of AIDS","volume":"27","author":"Jaffe","year":"2021","journal-title":"Emerg. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"636642","DOI":"10.3389\/fmicb.2021.636642","article-title":"Towards a Functional Cure of HIV-1: Insight Into the Chromatin Landscape of the Provirus","volume":"12","author":"Janssens","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1007\/s00018-018-2772-5","article-title":"Cellular and molecular mechanisms of HIV-1 integration targeting","volume":"75","author":"Engelman","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.3390\/v5071787","article-title":"Posttranslational modifications of HIV-1 integrase by various cellular proteins during viral replication","volume":"5","author":"Zheng","year":"2013","journal-title":"Viruses"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0167-4781(02)00241-5","article-title":"HIV-1 integrase interacts with yeast microtubule-associated proteins","volume":"1575","author":"Caumont","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1042\/BST20190331","article-title":"Towards a model of GCN2 activation","volume":"47","author":"Masson","year":"2019","journal-title":"Biochem. Soc. Trans."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.bbrc.2017.02.038","article-title":"A new role of GCN2 in the nucleolus","volume":"485","author":"Nakamura","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1007\/s00018-013-1272-x","article-title":"Activation of GCN2 upon HIV-1 infection and inhibition of translation","volume":"70","author":"Cosnefroy","year":"2013","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1038\/s41598-017-02276-0","article-title":"GCN2 phosphorylates HIV-1 integrase and decreases HIV-1 replication by limiting viral integration","volume":"7","author":"Jaspart","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/s41573-021-00195-4","article-title":"Kinase drug discovery 20 years after imatinib: Progress and future directions","volume":"20","author":"Cohen","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.bbrc.2020.05.045","article-title":"Identification of inhibitors of Bcl-2 family protein-protein interaction by combining the BRET screening platform with virtual screening","volume":"527","author":"Park","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.chembiol.2014.09.001","article-title":"Small-molecule inhibitors of protein-protein interactions: Progressing toward the reality","volume":"21","author":"Arkin","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ddtec.2017.10.004","article-title":"PPI inhibitor and stabilizer development in human diseases","volume":"24","author":"Bosch","year":"2017","journal-title":"Drug Discov. Today Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.drudis.2013.05.003","article-title":"iPPI-DB: A manually curated and interactive database of small non-peptide inhibitors of protein-protein interactions","volume":"18","author":"Labbe","year":"2013","journal-title":"Drug Discov. Today"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wu, K.J., Lei, P.M., Liu, H., Wu, C., Leung, C.H., and Ma, D.L. (2019). Mimicking Strategy for Protein-Protein Interaction Inhibitor Discovery by Virtual Screening. Molecules, 24.","DOI":"10.3390\/molecules24244428"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1517\/13543776.2014.898753","article-title":"LEDGINs, non-catalytic site inhibitors of HIV-1 integrase: A patent review (2006\u20132014)","volume":"24","author":"Demeulemeester","year":"2014","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1021\/ml500052f","article-title":"Triazolo[4,5-d]pyrimidine Derivatives as Inhibitors of GCN2","volume":"5","author":"Brazeau","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1124\/molpharm.120.000070","article-title":"GZD824 Inhibits GCN2 and Sensitizes Cancer Cells to Amino Acid Starvation Stress","volume":"98","author":"Kato","year":"2020","journal-title":"Mol. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1124\/mol.111.073189","article-title":"Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S\/GSK1349572)","volume":"80","author":"Hare","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.csbj.2018.09.003","article-title":"Triazolo[4,5-d]pyrimidines as Validated General Control Nonderepressible 2 (GCN2) Protein Kinase Inhibitors Reduce Growth of Leukemia Cells","volume":"16","author":"Lough","year":"2018","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_22","first-page":"209","article-title":"Efficacit\u00e9 de la s\u00e9quence th\u00e9rapeutique des inhibiteurs de tyrosine kinase (ITK) de 1re ou 2e g\u00e9n\u00e9ration suivie d\u2019osimertinib chez les patients atteints d\u2019un CBNPC m\u00e9tastatique avec mutation EGFR T790 M: TKISeq, une \u00e9tude fran\u00e7aise en vie r\u00e9elle","volume":"12","author":"Girard","year":"2020","journal-title":"Rev. Mal. Respir. Actual."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/bcpt.13537","article-title":"The tyrosine kinase inhibitor nilotinib inhibits SARS-CoV-2 in vitro","volume":"128","author":"Cagno","year":"2021","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.3389\/fonc.2020.01428","article-title":"Tyrosine Kinase Inhibitors Play an Antiviral Action in Patients Affected by Chronic Myeloid Leukemia: A Possible Model Supporting Their Use in the Fight Against SARS-CoV-2","volume":"10","author":"Galimberti","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mulgaonkar, N., Wang, H., Mallawarachchi, S., Fernando, S., Martina, B., and Ruzek, D. (2020). Bcr-Abl tyrosine kinase inhibitor imatinib as a potential drug for COVID-19. BioRxiv, 158196.","DOI":"10.1101\/2020.06.18.158196"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1021\/bi001660j","article-title":"Direct inhibition of the hexose transporter GLUT1 by tyrosine kinase inhibitors","volume":"40","author":"Vera","year":"2001","journal-title":"Biochemistry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.ejmech.2016.07.077","article-title":"Computational and synthetic approaches for developing Lavendustin B derivatives as allosteric inhibitors of HIV-1 integrase","volume":"123","author":"Agharbaoui","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e00012-17","DOI":"10.1128\/JVI.00012-17","article-title":"Maintenance of the HIV Reservoir Is Antagonized by Selective BCL2 Inhibition","volume":"91","author":"Cummins","year":"2017","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Alto, A., Natesampillai, S., Chandrasekar, A.P., Krogman, A., Misra, A., Shweta, F., VanLith, C., Yao, J.D., Cummins, N.W., and Badley, A.D. (2021). The Combination of Venetoclax and Ixazomib Selectively and Efficiently Kills HIV-Infected Cell Lines but Has Unacceptable Toxicity in Primary Cell Models. J. Virol., 95.","DOI":"10.1128\/JVI.00138-21"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1097\/00002030-199412000-00006","article-title":"The regulation of HIV by retinoic acid correlates with cellular expression of the retinoic acid receptors","volume":"8","author":"Yamaguchi","year":"1994","journal-title":"AIDS"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0083-6729(06)75013-0","article-title":"Effects of vitamins, including vitamin A, on HIV\/AIDS patients","volume":"75","author":"Mehta","year":"2007","journal-title":"Vitam. Horm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1080\/10245330701255130","article-title":"All-trans retinoic acid attacks reverse transcriptase resulting in inhibition of HIV-1 replication","volume":"12","author":"Maeda","year":"2007","journal-title":"Hematology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Malgras, M., Garcia, M., Jousselin, C., Bodet, C., and Leveque, N. (2021). The Antiviral Activities of Poly-ADP-Ribose Polymerases. Viruses, 13.","DOI":"10.3390\/v13040582"},{"key":"ref_34","first-page":"13","article-title":"Understanding mitotane mode of action","volume":"68","author":"Waszut","year":"2017","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1182\/blood.V75.3.696.696","article-title":"Effect of tamoxifen on regulation of viral replication and human immunodeficiency virus (HIV) long terminal repeat-directed transcription in cells chronically infected with HIV-1","volume":"75","author":"Laurence","year":"1990","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"25231","DOI":"10.1074\/jbc.275.33.25231","article-title":"Topoisomerase II is required for mitoxantrone to signal nuclear factor kappa B activation in HL60 cells","volume":"275","author":"Boland","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/med.21364","article-title":"Mitoxantrone, More than Just Another Topoisomerase II Poison","volume":"36","author":"Evison","year":"2016","journal-title":"Med. Res. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1073\/pnas.90.6.2399","article-title":"Inhibitors of human immunodeficiency virus integrase","volume":"90","author":"Fesen","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2100","DOI":"10.1021\/jm990322h","article-title":"Developing a dynamic pharmacophore model for HIV-1 integrase","volume":"43","author":"Carlson","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s13402-020-00544-2","article-title":"Mitoxantrone triggers immunogenic prostate cancer cell death via p53-dependent PERK expression","volume":"43","author":"Li","year":"2020","journal-title":"Cell Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e1466765","DOI":"10.1080\/2162402X.2018.1466765","article-title":"PKR and GCN2 stress kinases promote an ER stress-independent eIF2alpha phosphorylation responsible for calreticulin exposure in melanoma cells","volume":"7","author":"Giglio","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Aknin, C., Smith, E.A., Marchand, C., Andreola, M.L., Pommier, Y., and Metifiot, M. (2019). Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening. Molecules, 24.","DOI":"10.3390\/molecules24203675"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/17\/5423\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:57:26Z","timestamp":1760165846000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/17\/5423"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,6]]},"references-count":42,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["molecules26175423"],"URL":"https:\/\/doi.org\/10.3390\/molecules26175423","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,6]]}}}