Modelling the main cysteine proteinase of the SARS virus

Shoba Ranganathan¹, Victor Joo Chuan Tong²
¹shoba@bic.nus.edu.sg, National University of Singapore; ²victor@bic.nus.edu.sg, National University of Singapore

In March 2003, a novel coronavirus (SARS-CoV) was discovered in association with cases of severe acute respiratory syndrome (SARS), leading to progressive respiratory failure in 3-10% of cases. Worldwide research efforts are now focussing on the development of diagnostics, vaccines and antiviral therapeutics.

The key enzyme in coronavirus polyprotein processing and replication is the viral main cysteine proteinase (MPro), which shows hardly any similarity to other viral and cellular proteinases. With a knowledge of the SARS viral genome and the X-ray structure of MPro from the transmissible gastroenteritis (corona)virus, we have generated a structural model for the SARS MPro and analyzed its active site.

The preferred cleavage sites of MPro substrates and the putatative gene products from SARS-CoV are now known. Based on this data, we have generated several peptides representing MPro substrates and docked them into the enzyme active site.

What clues can be gleaned for designing MPro inhibitors as anti-SARS therapeutics, will be presented.