Hong Kong Med J 2014;20(Suppl 4):S18-21
Substrate specificity and rational design of peptidomimetic inhibitors for SARS coronavirus main protease
KB Wong, DCC Wan, HF Chow
School of Life Sciences, The Chinese University of Hong Kong
1. Substrate-specificity of the main protease of SARS coronavirus was systematically profiled at P5 to P3’ positions, which provided insights into a rational design of peptidomimetic inhibitors.
2. Leu and Gln were most favoured at P2 and P1 positions, respectively. Substrate preferences at P5 to P3 positions were important in enhancing the main protease activity. ‘Super-reactive’ substrate sequences were engineered, with more than a 2-fold increase in activity, by combining the best residue choices at P5 to P3 positions.
3. A novel class of peptidomimetic inhibitor against the main protease was developed using the nitrile warhead. The most potent inhibitor synthesised was Cbz-AVLQ-CN, with an IC50 value of 5 _M.
4. The crystal structure of the main protease in complex with Cbz-AVLQ-CN was determined, which provided structural insights into protease- inhibitor interactions for future structured-basis design of inhibitors.