Evaluation of metal‐conjugated compounds as inhibitors of 3CL protease of SARS‐CoV

3C‐like (3CL) protease is essential for the life cycle of severe acute respiratory syndrome‐coronavirus (SARS‐CoV) and therefore represents a key anti‐viral target. A compound library consisting of 960 commercially available drugs and biologically active substances was screened for inhibition of SARS‐CoV 3CL protease. Potent inhibition was achieved using the mercury‐containing compounds thimerosal and phenylmercuric acetate, as well as hexachlorophene. As well, 1–10 μM of each compound inhibited viral replication in Vero E6 cell culture. Detailed mechanism studies using a fluorescence‐based protease assay demonstrated that the three compounds acted as competitive inhibitors (K (i)=0.7, 2.4, and 13.7 μM for phenylmercuric acetate, thimerosal, and hexachlorophene, respectively). A panel of metal ions including Zn(2+) and its conjugates were then evaluated for their anti‐3CL protease activities. Inhibition was more pronounced using a zinc‐conjugated compound (1‐hydroxypyridine‐2‐thione zinc; [Image: see text] M) than using the ion alone ([Image: see text] M).