Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system

Pharmacol Res. 2020 Sep;159:104960. doi: 10.1016/j.phrs.2020.104960. Epub 2020 May 28.

Abstract

Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50 % maximal effective concentrations (EC50) that exceeded their achievable peak serum concentrations (Cmax), side effects, and/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC50 1.13-2.01 μM). Bexarotene demonstrated the highest Cmax:EC50 ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.

Keywords: Abiraterone; Abiraterone acetate (PubChem CID: 9821849); Antiviral; Bexarotene; Bexarotene (PubChem CID: 82146); COVID-19; Cetilistat; Cetilistat (PubChem CID: 9952916); Coronavirus; Diiodohydroxyquinoline; Diiodohydroxyquinoline (PubChem CID: 3728); Library; SARS-CoV-2; Treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenes / pharmacology
  • Animals
  • Antiviral Agents / pharmacology*
  • Benzoxazines / pharmacology
  • Betacoronavirus* / drug effects
  • Betacoronavirus* / physiology
  • Bexarotene / pharmacology
  • COVID-19
  • Caco-2 Cells
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology
  • Cytopathogenic Effect, Viral / drug effects
  • Databases, Pharmaceutical
  • Drug Approval
  • Drug Evaluation, Preclinical / methods*
  • Drug Repositioning
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Iodoquinol / pharmacology
  • Pandemics
  • Pneumonia, Viral / drug therapy*
  • Pneumonia, Viral / virology
  • SARS-CoV-2
  • United States
  • United States Food and Drug Administration
  • Vero Cells
  • Viral Load / drug effects
  • Virus Replication / drug effects

Substances

  • Androstenes
  • Antiviral Agents
  • Benzoxazines
  • Iodoquinol
  • Bexarotene
  • abiraterone
  • cetilistat

Supplementary concepts

  • COVID-19 drug treatment