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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 09; 159:104960.PR

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+Show Affiliations

State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region; Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China; Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, China; and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region. Electronic address: jfwchan@hku.hk.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, China; and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Department of Pathogen Biology, Hainan Medical University, Haikou, Hainan, China; Key Laboratory of Translational Tropical Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan, China.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region.School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region.State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region; Centre for Virology, Vaccinology and Therapeutics, Health@InnoHK, The University of Hong Kong, Hong Kong Special Administrative Region; Department of Clinical Microbiology and Infection Control, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong Province, China; Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, China; and The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region. Electronic address: kyyuen@hku.hk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32473310

Citation

Yuan, Shuofeng, et al. "Discovery of the FDA-approved Drugs Bexarotene, Cetilistat, Diiodohydroxyquinoline, and Abiraterone as Potential COVID-19 Treatments With a Robust Two-tier Screening System." Pharmacological Research, vol. 159, 2020, p. 104960.
Yuan S, Chan JFW, Chik KKH, et al. 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;159:104960.
Yuan, S., Chan, J. F. W., Chik, K. K. H., Chan, C. C. Y., Tsang, J. O. L., Liang, R., Cao, J., Tang, K., Chen, L. L., Wen, K., Cai, J. P., Ye, Z. W., Lu, G., Chu, H., Jin, D. Y., & Yuen, K. Y. (2020). Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system. Pharmacological Research, 159, 104960. https://doi.org/10.1016/j.phrs.2020.104960
Yuan S, et al. 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;159:104960. PubMed PMID: 32473310.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system. AU - Yuan,Shuofeng, AU - Chan,Jasper F W, AU - Chik,Kenn K H, AU - Chan,Chris C Y, AU - Tsang,Jessica O L, AU - Liang,Ronghui, AU - Cao,Jianli, AU - Tang,Kaiming, AU - Chen,Lin-Lei, AU - Wen,Kun, AU - Cai,Jian-Piao, AU - Ye,Zi-Wei, AU - Lu,Gang, AU - Chu,Hin, AU - Jin,Dong-Yan, AU - Yuen,Kwok-Yung, Y1 - 2020/05/28/ PY - 2020/04/09/received PY - 2020/05/20/revised PY - 2020/05/24/accepted PY - 2020/5/31/pubmed PY - 2020/9/12/medline PY - 2020/5/31/entrez KW - Abiraterone KW - Abiraterone acetate (PubChem CID: 9821849) KW - Antiviral KW - Bexarotene KW - Bexarotene (PubChem CID: 82146) KW - COVID-19 KW - Cetilistat KW - Cetilistat (PubChem CID: 9952916) KW - Coronavirus KW - Diiodohydroxyquinoline KW - Diiodohydroxyquinoline (PubChem CID: 3728) KW - Library KW - SARS-CoV-2 KW - Treatment SP - 104960 EP - 104960 JF - Pharmacological research JO - Pharmacol Res VL - 159 N2 - 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. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/32473310/Discovery_of_the_FDA_approved_drugs_bexarotene_cetilistat_diiodohydroxyquinoline_and_abiraterone_as_potential_COVID_19_treatments_with_a_robust_two_tier_screening_system_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(20)31268-8 DB - PRIME DP - Unbound Medicine ER -