Development of broad-spectrum enterovirus antivirals based on quinoline scaffold

Rami Musharrafieh, Naoya Kitamura, Yanmei Hu, Jun Wang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Non-polio enteroviruses such as enterovirus A71 (EV-A71), EV-D68, and coxsackievirus B3 (CVB3) are significant human pathogens with disease manifestations ranging from mild flu-like symptoms to more severe encephalitis, myocarditis, acute flaccid paralysis/myelitis, and even death. There is currently no effective antivirals to prevent or treat non-polio enterovirus infection. In this study, we report our progress in developing potent and broad-spectrum antivirals against these non-polio enteroviruses. Starting from our previously developed lead compounds that had potent antiviral activity against EV-D68, we synthesized 43 analogs and profiled their broad-spectrum antiviral activity against additional EV-D68, EV-A71, and CVB3 viruses. Promising candidates were also selected for mouse microsomal stability test to prioritize lead compounds for future in vivo mouse model studies. Collectively, this multi-parameter optimization process revealed a promising lead compound 6aw that showed single-digit to submicromolar EC50 values against two EV-D68 strains (US/KY and US/MO), two EV-A71 strains (Tainan and US/AK), and one CVB3 strain, with a high selectivity index. Encouragingly, 6aw was stable in mouse microsomes with a half-life of 114.7 min. Overall, 6aw represents one of the most potent broad-spectrum antiviral against non-polio enteroviruses, rendering it a promising lead candidate for non-polio enteroviruses with translational potential.

Original languageEnglish (US)
Article number103981
JournalBioorganic Chemistry
Volume101
DOIs
StatePublished - Aug 2020

Keywords

  • A71
  • Antiviral
  • Coxsackievirus B3
  • D68
  • Enterovirus
  • Quinoline

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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