1. Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome
- Author
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Haiying Chen, Jerónimo Pachón, Judith Berastegui-Cabrera, Javier Sánchez-Céspedes, Marta Carretero-Ledesma, Eric A. Wold, Jimin Xu, Jia Zhou, Yu Xue, Universidad de Sevilla. Departamento de Medicina, [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., and This 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.
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entry inhibition ,0301 basic medicine ,Salicylamide ,Virus Replication ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,lcsh:Chemistry ,Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Small Molecule Libraries [Medical Subject Headings] ,Drug Discovery ,Salicylamides ,Antivíricos ,lcsh:QH301-705.5 ,Spectroscopy ,Niclosamide ,Infecciones ,Chemistry ,virus diseases ,adenovirus ,General Medicine ,Chemicals and Drugs::Organic Chemicals::Amides::Anilides::Salicylanilides::Niclosamide [Medical Subject Headings] ,Small molecule ,Virus ,Computer Science Applications ,Organisms::Viruses::DNA Viruses::Adenoviridae::Mastadenovirus::Adenoviruses, Human [Medical Subject Headings] ,Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed::HEK293 Cells [Medical Subject Headings] ,Lytic cycle ,Phenomena and Processes::Microbiological Phenomena::Virus Physiological Phenomena::Virus Physiological Processes::Virus Internalization [Medical Subject Headings] ,salicylamide derivatives ,Niclosamida ,medicine.drug ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery [Medical Subject Headings] ,medicine.drug_class ,Endosome ,Chemicals and Drugs::Organic Chemicals::Amides::Salicylamides [Medical Subject Headings] ,030106 microbiology ,Endosomes ,Antiviral Agents ,Endosomas ,Article ,Catalysis ,Adenoviridae ,Small Molecule Libraries ,antiviral agent ,Inorganic Chemistry ,Inhibitory Concentration 50 ,03 medical and health sciences ,Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Transport Vesicles::Endosomes [Medical Subject Headings] ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50 [Medical Subject Headings] ,medicine ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Adenoviruses, Human ,Organic Chemistry ,Virus Internalization ,Virology ,eye diseases ,Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Viral Tropism [Medical Subject Headings] ,Viral Tropism ,Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Virus Replication [Medical Subject Headings] ,HEK293 Cells ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,A549 Cells ,Tissue tropism ,Antiviral drug - Abstract
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 >, 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.
- Published
- 2021
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