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

Autor: Shuofeng Yuan, Ronghui Liang, Jessica Oi-Ling Tsang, Kwok-Yung Yuen, Hin Chu, Jian Piao Cai, Jianli Cao, Kaiming Tang, Zi-Wei Ye, Dong-Yan Jin, Gang Lu, Jasper Fuk-Woo Chan, Kenn K.H. Chik, Kun Wen, Lin Lei Chen, Chris Chun-Yiu Chan
Rok vydání: 2020
Předmět:
0301 basic medicine
Databases
Pharmaceutical
coronavirus
Drug Evaluation
Preclinical
Pharmacology
Virus Replication
chemistry.chemical_compound
0302 clinical medicine
Cetilistat
Cytopathogenic Effect
Viral
abiraterone
Chlorocebus aethiops
Medicine
Drug Approval
media_common
Bexarotene
treatment
Diiodohydroxyquinoline (PubChem CID: 3728)
Abiraterone acetate
Viral Load
antiviral
030220 oncology & carcinogenesis
Androstenes
Coronavirus Infections
medicine.drug
Camostat
Drug
diiodohydroxyquinoline
Bexarotene (PubChem CID: 82146)
Cell Survival
media_common.quotation_subject
Pneumonia
Viral
Cmax
Enzyme-Linked Immunosorbent Assay
Antiviral Agents
Article
cetilistat
Betacoronavirus
03 medical and health sciences
Pharmacokinetics
Iodoquinol
Animals
Humans
Pandemics
Vero Cells
ComputingMethodologies_COMPUTERGRAPHICS
Cetilistat (PubChem CID: 9952916)
SARS-CoV-2
United States Food and Drug Administration
business.industry
bexarotene
Drug Repositioning
COVID-19
library
Hydroxychloroquine
United States
Benzoxazines
COVID-19 Drug Treatment
030104 developmental biology
chemistry
Abiraterone acetate (PubChem CID: 9821849)
Caco-2 Cells
business
Zdroj: Pharmacological Research
ISSN: 1043-6618
DOI: 10.1016/j.phrs.2020.104960
Popis: Graphical 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 1.13-2.01µM). 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.
Databáze: OpenAIRE
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