1. Academic Validation
  2. Development of broad-spectrum enterovirus antivirals based on quinoline scaffold

Development of broad-spectrum enterovirus antivirals based on quinoline scaffold

  • Bioorg Chem. 2020 Aug;101:103981. doi: 10.1016/j.bioorg.2020.103981.
Rami Musharrafieh 1 Naoya Kitamura 2 Yanmei Hu 2 Jun Wang 3
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States; Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States.
  • 2 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States.
  • 3 Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721, United States. Electronic address: junwang@pharmacy.arizona.edu.
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.

Keywords

A71; Antiviral; Coxsackievirus B3; D68; Enterovirus; Quinoline.

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