Discovery of Potent Anti-SARS-CoV MPro Inhibitors

SARS is a viral respiratory illness caused by a previously unrecognized coronavirus, called SARS-associated coronavirus (SARS-CoV). Because of the potential for a rapid spread of the disease, it is vitally important to identify drugs that effectively inhibit a known target of the SARS coronavirus. Because of its essential role in proteolytic processing, the main protease MPro, a cysteine protease, is considered an attractive target for antiviral drugs against SARS and other coronavirus infections. In this review, we will present both peptidic and non-peptidic inhibitors that have been designed against SARS MPro. The most challenging requirement in designing cysteine inhibitors is to obtain a selective non-covalent electrophilic isostere that can react with the catalytic nucleophile. Emphasis will be put on our recent results, both experimental and theoretical, in the search for potent wide-spectrum inhibitors. The antiviral activity of the octopeptide AVLQSGFR against SARS-associated coronavirus will be presented as well as the recent hits obtained from virtual high throughput screening (vHTS) based on the identification of six hydrogen bond pharmacophore points from KZ7088 docked into the active site of SARS MPro.