{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T19:04:57Z","timestamp":1781723097095,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Network for Research in Infectious Diseases","award":["REIPI RD16\/0016\/0009"],"award-info":[{"award-number":["REIPI RD16\/0016\/0009"]}]},{"name":"Spanish Adenovirus Network","award":["AdenoNet, BIO2015\/68990-REDT"],"award-info":[{"award-number":["AdenoNet, BIO2015\/68990-REDT"]}]},{"name":"Nicol\u00e1s Monardes","award":["C-0059-2018"],"award-info":[{"award-number":["C-0059-2018"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["F31 DA04551"],"award-info":[{"award-number":["F31 DA04551"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008013","name":"UTMB","doi-asserted-by":"publisher","award":["John D. Stobo, M. D. Distinguished Chair Endowment Fund"],"award-info":[{"award-number":["John D. Stobo, M. D. Distinguished Chair Endowment Fund"]}],"id":[{"id":"10.13039\/100008013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human adenoviruses (HAdVs) display a wide range of tissue tropism and can cause an array of symptoms from mild respiratory illnesses to disseminated and life-threatening infections in immunocompromised individuals. However, no antiviral drug has been approved specifically for the treatment of HAdV infections. Herein, we report our continued efforts to optimize salicylamide derivatives and discover compound 16 (JMX0493) as a potent inhibitor of HAdV infection. Compound 16 displays submicromolar IC50 values, a higher selectivity index (SI &gt; 100) and 2.5-fold virus yield reduction compared to our hit compound niclosamide. Moreover, unlike niclosamide, our mechanistic studies suggest that the antiviral activity of compound 16 against HAdV is achieved through the inhibition of viral particle escape from the endosome, which bars subsequent uncoating and the presentation of lytic protein VI.<\/jats:p>","DOI":"10.3390\/ijms22041617","type":"journal-article","created":{"date-parts":[[2021,2,7]],"date-time":"2021-02-07T14:04:13Z","timestamp":1612706653000},"page":"1617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-7263","authenticated-orcid":false,"given":"Jimin","family":"Xu","sequence":"first","affiliation":[{"name":"Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Berastegui-Cabrera","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, E41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Carretero-Ledesma","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, E41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Chen","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xue","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6434-7562","authenticated-orcid":false,"given":"Eric A.","family":"Wold","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8166-5308","authenticated-orcid":false,"given":"Jer\u00f3nimo","family":"Pach\u00f3n","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, E41013 Seville, Spain"},{"name":"Department of Medicine, University of Seville, E-41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-1090","authenticated-orcid":false,"given":"Jia","family":"Zhou","sequence":"additional","affiliation":[{"name":"Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2707-1979","authenticated-orcid":false,"given":"Javier","family":"S\u00e1nchez-C\u00e9spedes","sequence":"additional","affiliation":[{"name":"Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Roc\u00edo, CSIC, University of Seville, E41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1038\/srep01812","article-title":"Molecular evolution of human adenoviruses","volume":"3","author":"Robinson","year":"2013","journal-title":"Sci. Rep."},{"key":"ref_2","unstructured":"(2020, January 22). HAdV Working Group Human Adenovirus Working Group. Available online: http:\/\/hadvwg.gmu.edu\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1128\/CMR.00052-07","article-title":"Adenoviruses in immunocompromised hosts","volume":"21","author":"Echavarria","year":"2008","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1128\/CMR.00116-13","article-title":"Adenovirus infections in immunocompetent and immunocompromised patients","volume":"27","author":"Lion","year":"2014","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ijid.2017.07.011","article-title":"Respiratory viruses in transplant recipients: More than just a cold. Clinical syndromes and infection prevention principles","volume":"62","author":"Abbas","year":"2017","journal-title":"Int. J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1007\/s11908-014-0416-y","article-title":"Adenovirus: Current epidemiology and emerging approaches to prevention and treatment","volume":"16","author":"Sandkovsky","year":"2014","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.bbmt.2018.12.753","article-title":"Incidence of adenovirus infection in hematopoietic stem cell transplantation recipients: Findings from the advance study","volume":"25","author":"Petterson","year":"2019","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jonnalagadda, S., Rodr\u00edguez, O., Estrella, B., Sabin, L.L., Semp\u00e9rtegui, F., and Hamer, D.H. (2017). Etiology of severe pneumonia in Ecuadorian children. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171687"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"730","DOI":"10.3201\/eid2204.151403","article-title":"Severe infections with human adenovirus 7d in 2 adults in family, Illinois, USA, 2014","volume":"22","author":"Kajon","year":"2016","journal-title":"Emerg. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"848","DOI":"10.21037\/jtd.2016.03.38","article-title":"Severe adenovirus community-acquired pneumonia in immunocompetent adults: Chest radiographic and CT findings","volume":"8","author":"Tan","year":"2016","journal-title":"J. Thorac. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Tan, D., Zhu, H., Fu, Y., Tong, F., Yao, D., Walline, J., Xu, J., and Yu, X. (2016). Severe community-acquired pneumonia caused by human adenovirus in immunocompetent adults: A multicenter case series. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151199"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Yoon, B.W., Song, Y.G., and Lee, S.H. (2017). Severe community-acquired adenovirus pneumonia treated with oral ribavirin: A case report. BMC Res. Notes, 10.","DOI":"10.1186\/s13104-016-2370-2"},{"key":"ref_13","first-page":"19051","article-title":"Clinical data analysis of 19 cases of community-acquired adenovirus pneumonia in immunocompetent adults","volume":"8","author":"Yu","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/rmv.589","article-title":"Clinical features and treatment of adenovirus infections","volume":"18","author":"Lenaerts","year":"2008","journal-title":"Rev. Med. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.drudis.2015.07.007","article-title":"Antiadenovirus drug discovery: Potential targets and evaluation methodologies","volume":"20","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1093\/femsre\/fuz008","article-title":"Drug development against human adenoviruses and its advancement by Syrian hamster models","volume":"43","author":"Wold","year":"2019","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3871","DOI":"10.1128\/AAC.00203-10","article-title":"Small-molecule screening using a whole-cell viral replication reporter gene assay identifies 2-{[2-(benzoylamino)benzoyl]amino}-benzoic acid as a novel antiadenoviral compound","volume":"54","author":"Andersson","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1021\/jm201636v","article-title":"Synthesis, biological evaluation, and structure-activity relationships of 2-[2-(benzoylamino)benzoylamino]benzoic acid analogues as inhibitors of adenovirus replication","volume":"55","author":"Oberg","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.antiviral.2014.05.010","article-title":"Inhibition of adenovirus replication by a trisubstituted piperazin-2-one derivative","volume":"108","author":"Moyer","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5432","DOI":"10.1021\/acs.jmedchem.6b00300","article-title":"New 4-acyl-1-phenylaminocarbonyl-2-phenylpiperazine derivatives as potential inhibitors of adenovirus infection. Synthesis, biological evaluation, and structure-activity relationships","volume":"59","author":"Candela","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"111840","DOI":"10.1016\/j.ejmech.2019.111840","article-title":"Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents","volume":"185","author":"Mazzotta","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e01925-18","DOI":"10.1128\/AAC.01925-18","article-title":"Cidofovir diphosphate inhibits adenovirus 5 DNA polymerase via both nonobligate chain termination and direct inhibition, and polymerase mutations confer cidofovir resistance on intact virus","volume":"63","author":"Chamberlain","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.antiviral.2009.01.005","article-title":"Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: Current state of the art","volume":"82","author":"Hostetler","year":"2009","journal-title":"Antivir. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1097\/FTD.0000000000000353","article-title":"Brincidofovir is not a substrate for the human organic anion transporter 1: A mechanistic explanation for the lack of nephrotoxicity observed in clinical studies","volume":"38","author":"Tippin","year":"2016","journal-title":"Ther. Drug Monit."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7293","DOI":"10.1073\/pnas.0800200105","article-title":"Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model","volume":"105","author":"Toth","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.bbmt.2014.11.136","article-title":"Preliminary results from the advise study evaluating brincidofovir (CMX001, BCV) for the treatment of disseminated and high-risk adenovirus (AdV) infection","volume":"21","author":"Grimley","year":"2015","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.bbmt.2017.01.062","article-title":"46-Treatment of adenovirus (AdV) infection in allogeneic hematopoietic cell transplant (allo HCT) patients (pts) with brincidofovir: Final 36 week results from the advise trial","volume":"23","author":"Prasad","year":"2017","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.antiviral.2017.01.009","article-title":"Short-term clinical safety profile of brincidofovir: A favorable benefit\u2013risk proposition in the treatment of smallpox","volume":"143","author":"Chittick","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.bbmt.2016.12.621","article-title":"Brincidofovir for asymptomatic adenovirus viremia in pediatric and adult allogeneic hematopoietic cell transplant recipients: A randomized placebo-controlled phase II trial","volume":"23","author":"Grimley","year":"2017","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.tube.2019.04.008","article-title":"Dual activity of niclosamide to suppress replication of integrated HIV-1 and Mycobacterium tuberculosis (Beijing)","volume":"116","author":"Fan","year":"2019","journal-title":"Tuberculosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7941","DOI":"10.1021\/acs.jmedchem.9b00698","article-title":"Design, synthesis, and biological evaluation of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3\u2019-indoline]-2\u2019,5(3H)-dione analogues as potent NS4B inhibitors for the treatment of dengue virus infection","volume":"62","author":"Xu","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1172\/JCI120633","article-title":"Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV","volume":"129","author":"Niu","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1021\/acsinfecdis.6b00041","article-title":"Therapeutic potential of spirooxindoles as antiviral agents","volume":"2","author":"Ye","year":"2016","journal-title":"ACS Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1021\/acsinfecdis.0c00052","article-title":"Broad spectrum antiviral agent niclosamide and its therapeutic potential","volume":"6","author":"Xu","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1021\/acsinfecdis.0c00217","article-title":"JMX0207, a niclosamide derivative with improved pharmacokinetics, suppresses ZIKA virus infection both in vitro and in vivo","volume":"6","author":"Li","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"127162","DOI":"10.1016\/j.bmcl.2020.127162","article-title":"Design, synthesis and biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors","volume":"30","author":"Xu","year":"2020","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41598-018-37290-3","article-title":"Repositioning salicylanilide anthelmintic drugs to treat adenovirus infections","volume":"9","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1021\/acs.jmedchem.9b01950","article-title":"Structure\u2013activity relationship studies on diversified salicylamide derivatives as potent inhibitors of human adenovirus infection","volume":"63","author":"Xu","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12830","DOI":"10.1021\/acs.jmedchem.0c01226","article-title":"Discovery of novel substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent human adenovirus inhibitors","volume":"63","author":"Xu","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1128\/JVI.79.4.1992-2000.2005","article-title":"Adenovirus protein VI mediates membrane disruption following capsid disassembly","volume":"79","author":"Wiethoff","year":"2005","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1006\/viro.1995.1240","article-title":"Proline 137 is critical for adenovirus protease encapsidation and activation but not enzyme activity","volume":"209","author":"Rancourt","year":"1995","journal-title":"Virology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.chom.2007.12.001","article-title":"Mechanism of adenovirus neutralization by Human \u03b1-defensins","volume":"3","author":"Smith","year":"2008","journal-title":"Cell Host Microbe"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.chom.2015.06.006","article-title":"Co-option of membrane wounding enables virus penetration into cells","volume":"18","author":"Luisoni","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Matthews, H., Deakin, J., Rajab, M., Idris-Usman, M., and Nirmalan, N.J. (2017). Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173303"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1128\/JVI.02471-09","article-title":"Direct evidence from single-cell analysis that human \u03b1-defensins block adenovirus uncoating to neutralize infection","volume":"84","author":"Nguyen","year":"2010","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/sj.mt.6300048","article-title":"Enhancement of gene transfer to human myeloid cells by adenovirus-fiber complexes","volume":"15","author":"Nepomuceno","year":"2007","journal-title":"Mol. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Meth."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1093\/oxfordjournals.aje.a118408","article-title":"A simple method of estimating fifty per cent endpoints","volume":"27","author":"Reed","year":"1938","journal-title":"Am. J. Epidemiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.virol.2003.11.028","article-title":"Mode of transgene expression after fusion to early or late viral genes of a conditionally replicating adenovirus via an optimized internal ribosome entry site in vitro and in vivo","volume":"320","author":"Rivera","year":"2004","journal-title":"Virology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1617\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:20:09Z","timestamp":1760160009000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,5]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041617"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041617","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,5]]}}}