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

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.

• Authors: Jimin Xu, Judith Berastegui-Cabrera, Marta Carretero-Ledesma, Haiying Chen, Yu Xue, Eric A Wold, Jerónimo Pachón, Jia Zhou, Javier Sánchez-Céspedes
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 4 (Feb 05 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33562748 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Salicylamides
• Small Molecule Libraries
• Niclosamide

Topics

• A549 Cells
• Adenoviruses, Human (drug effects, physiology)
• Antiviral Agents (pharmacology)
• Drug Discovery
• Endosomes (drug effects, virology)
• HEK293 Cells
• Humans
• Inhibitory Concentration 50
• Niclosamide (chemistry, pharmacology)
• Salicylamides (chemistry, pharmacology)
• Small Molecule Libraries (chemistry, pharmacology)
• Viral Tropism
• Virus Internalization (drug effects)
• Virus Replication (drug effects)