Discovery of a small molecule inhibitor of human adenovirus capable of preventing escape from the endosome

Jimin Xu, Judith Berastegui-Cabrera, Marta Carretero-Ledesma, Haiying Chen, Yu Xue, Eric A. Wold, Jerónimo Pachón, Jia Zhou, Javier Sánchez-Céspedes

Research output: Contribution to journalArticlepeer-review

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 salicy-lamide 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.

Original languageEnglish (US)
Article number1617
Pages (from-to)1-21
Number of pages21
JournalInternational journal of molecular sciences
Volume22
Issue number4
DOIs
StatePublished - Feb 2 2021

Keywords

  • Adenovirus
  • Antiviral agent
  • Entry inhibition
  • Salicylamide derivatives

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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