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Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome

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dc.contributor.authorXu, Jimin
dc.contributor.authorBerastegui-Cabrera, Judith
dc.contributor.authorCarretero-Ledesma, Marta
dc.contributor.authorChen, Haiying
dc.contributor.authorXue, Yu
dc.contributor.authorWold, Eric A.
dc.contributor.authorPachón, Jerónimo
dc.contributor.authorZhou, Jia
dc.contributor.authorSánchez-Céspedes, Javier
dc.contributor.authoraffiliation[Xu,J; Chen,H; Xue,Y; Wold,EA; Zhou,J] Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX, USA. [Berastegui-Cabrera,J; Carretero-Ledesma,M; Pachón,J; Sánchez-Céspedes,J] Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain. [Pachón,J] Department of Medicine, University of Seville, Seville, Spain.
dc.contributor.funderThis work was partially supported by the UTMB Technology Commercialization Program, the John D. Stobo, M. D. Distinguished Chair Endowment Fund (to JZ) and John Sealy Memorial Endowment Fund at UTMB, Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), cofinanced by the European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 20142020, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI15/00489) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT), and the program “Nicolás Monardes” (C-0059-2018) Servicio Andaluz de Salud, Junta de Andalucía. E.A.W. is supported by the National Institutes of Health (NIH) National Research Service Award (NRSA) F31 DA04551.
dc.date.accessioned2022-08-09T06:02:53Z
dc.date.available2022-08-09T06:02:53Z
dc.date.issued2021-02-05
dc.description.abstractHuman 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 > 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.es_ES
dc.description.versionYeses_ES
dc.identifier.citationXu J, Berastegui-Cabrera J, Carretero-Ledesma M, Chen H, Xue Y, Wold EA, et al. Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome. Int J Mol Sci. 2021 Feb 5;22(4):1617es_ES
dc.identifier.doi10.3390/ijms22041617es_ES
dc.identifier.essn1422-0067
dc.identifier.pmcPMC7915867
dc.identifier.pmid33562748es_ES
dc.identifier.urihttp://hdl.handle.net/10668/3893
dc.journal.titleInternational Journal of Molecular Sciences
dc.language.isoen
dc.page.number21 p.
dc.publisherMDPIes_ES
dc.relation.publisherversionhttps://www.mdpi.com/1422-0067/22/4/1617/htmes_ES
dc.rightsAtribución 4.0 Internacional*
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAntiviral agentes_ES
dc.subjectAdenoviruses_ES
dc.subjectSalicylamide derivativeses_ES
dc.subjectEntry inhibitiones_ES
dc.subjectAntivíricoses_ES
dc.subjectAdenoviridaees_ES
dc.subjectEndosomases_ES
dc.subjectInfeccioneses_ES
dc.subjectViruses_ES
dc.subjectNiclosamidaes_ES
dc.subject.meshMedical Subject Headings::Organisms::Viruses::DNA Viruses::Adenoviridae::Mastadenovirus::Adenoviruses, Humanes_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agentses_ES
dc.subject.meshMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discoveryes_ES
dc.subject.meshMedical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Transport Vesicles::Endosomeses_ES
dc.subject.meshMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed::HEK293 Cellses_ES
dc.subject.meshMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humanses_ES
dc.subject.meshMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50es_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Anilides::Salicylanilides::Niclosamidees_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Salicylamideses_ES
dc.subject.meshMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Small Molecule Librarieses_ES
dc.subject.meshMedical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Viral Tropismes_ES
dc.subject.meshMedical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Virus Physiological Phenomena::Virus Physiological Processes::Virus Internalizationes_ES
dc.subject.meshMedical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Virus Replicationes_ES
dc.titleDiscovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosomees_ES
dc.typeresearch article
dc.type.hasVersionVoR
dspace.entity.typePublication

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