Esculatin‐4‐carboxylic acid ethyl ester: A novel class of marine‐derived anti‐SARS‐coronavirus 3CL protease inhibitors

Abstract

Marine sponges, which produce a remarkable array of secondary metabolites with pharmaceutical potential, are currently under investigation for cancer/pain treatments and anti-viral therapy. This study describes our discovery of the first small-molecule protease inhibitor from a marine organism directed at the Severe Acute Respiratory Syndrome (SARS)-associated coronovirus 3CL protease. By analogy with other coronaviruses, SARS-CoV encodes a main protease, 3CL, that plays an essential role in the viral life cycle and is currently the prime target for development of new anti-coronavirus agents. The inhibitory compound was identified as esculatin-4-carboxylic acid ethyl ester (MC8: ID50 = 46 □ M), a novel coumarin derivative extracted from the tropical marine sponge Axinella cf. corrugata, an important model of marine organism. Using a cell-culture-based assay of SARS-CoV infection, we demonstrated that MC8 is an anti-SARS agent with an EC50 of 112□ M and a median toxic concentration higher than 800 □M. We are currently synthesizing new analogs of the MC8 coumarin compound and are evaluating their mechanism of inhibition and anti-SARS-CoV effects. The results of our work underscore the importance of screening chemically diverse metabolite libraries, obtained from marine sponges, for the discovery of novel protease inhibitors with potent antiviral activities and a good therapeutic index. Supported by CIHR (F. Jean).