Publication: Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome
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Date
2021-02-05
Authors
Xu, Jimin
Berastegui-Cabrera, Judith
Carretero-Ledesma, Marta
Chen, Haiying
Xue, Yu
Wold, Eric A.
Pachón, Jerónimo
Zhou, Jia
Sánchez-Céspedes, Javier
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MDPI
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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.
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MeSH Terms
Medical Subject Headings::Organisms::Viruses::DNA Viruses::Adenoviridae::Mastadenovirus::Adenoviruses, Human
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Transport Vesicles::Endosomes
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed::HEK293 Cells
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Anilides::Salicylanilides::Niclosamide
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Salicylamides
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Small Molecule Libraries
Medical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Viral Tropism
Medical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Virus Physiological Phenomena::Virus Physiological Processes::Virus Internalization
Medical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Virus Replication
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery
Medical Subject Headings::Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Transport Vesicles::Endosomes
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Transformed::HEK293 Cells
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Toxicity Tests::Inhibitory Concentration 50
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Anilides::Salicylanilides::Niclosamide
Medical Subject Headings::Chemicals and Drugs::Organic Chemicals::Amides::Salicylamides
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Small Molecule Libraries
Medical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Viral Tropism
Medical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Virus Physiological Phenomena::Virus Physiological Processes::Virus Internalization
Medical Subject Headings::Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Virus Physiological Processes::Virus Replication
DeCS Terms
CIE Terms
Keywords
Antiviral agent, Adenovirus, Salicylamide derivatives, Entry inhibition, Antivíricos, Adenoviridae, Endosomas, Infecciones, Virus, Niclosamida
Citation
Xu 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):1617