Small molecules targeting severe acute respiratory syndrome human coronavirus.
Severe acute respiratory syndrome (SARS) is an infectious disease caused by a novel human coronavirus. Currently, no effective antiviral agents exist against this type of virus. A cell-based assay, with SARS virus and Vero E6 cells, was developed to screen existing drugs, natural products, and synthetic compounds to identify effective anti-SARS agents. Of >10,000 agents tested, approximately 50 compounds were found active at 10 microM; among these compounds, two are existing drugs (Reserpine 13 and Aescin 5) and several are in clinical development. These 50 active compounds were tested again, and compounds 2-6, 10, and 13 showed active at 3 microM. The 50% inhibitory concentrations for the inhibition of viral replication (EC(50)) and host growth (CC(50)) were then measured and the selectivity index (SI = CC(50)/EC(50)) was determined. The EC(50), based on ELISA, and SI for Reserpine, Aescim, and Valinomycin are 3.4 microM (SI = 7.3), 6.0 microM (SI = 2.5), and 0.85 microM (SI = 80), respectively. Additional studies were carried out to further understand the mode of action of some active compounds, including ELISA, Western blot analysis, immunofluorescence and flow cytometry assays, and inhibition against the 3CL protease and viral entry. Of particular interest are the two anti-HIV agents, one as an entry blocker and the other as a 3CL protease inhibitor (K(i) = 0.6 microM).
Wu
Chung-Yi
CY
Genomics Research Center and Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Jan
Jia-Tsrong
JT
Ma
Shiou-Hwa
SH
Kuo
Chih-Jung
CJ
Juan
Hsueh-Fen
HF
Cheng
Yih-Shyun E
YS
Hsu
Hsien-Hua
HH
Huang
Hsuan-Cheng
HC
Wu
Douglass
D
Brik
Ashraf
A
Liang
Fu-Sen
FS
Liu
Rai-Shung
RS
Fang
Jim-Min
JM
Chen
Shui-Tein
ST
Liang
Po-Huang
PH
Wong
Chi-Huey
CH
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002522:Chlorocebus aethiops; D000086782:Coronavirus 3C Proteases; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D014764:Viral Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086782:Coronavirus 3C Proteases