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

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.

• Authors: Shuofeng Yuan, Jasper F W Chan, Kenn K H Chik, Chris C Y Chan, Jessica O L Tsang, Ronghui Liang, Jianli Cao, Kaiming Tang, Lin-Lei Chen, Kun Wen, Jian-Piao Cai, Zi-Wei Ye, Gang Lu, Hin Chu, Dong-Yan Jin, Kwok-Yung Yuen
• Journal: Pharmacological research (Pharmacol Res) Vol. 159 Pg. 104960 (09 2020) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 32473310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

• Androstenes (pharmacology)
• Animals
• Antiviral Agents (pharmacology)
• Benzoxazines (pharmacology)
• Betacoronavirus (drug effects, physiology)
• Bexarotene (pharmacology)
• COVID-19
• Caco-2 Cells
• Cell Survival (drug effects)
• Chlorocebus aethiops
• Coronavirus Infections (drug therapy, 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, virology)
• SARS-CoV-2
• United States
• United States Food and Drug Administration
• Vero Cells
• Viral Load (drug effects)
• Virus Replication (drug effects)
• COVID-19 Drug Treatment