Polyprotein cleavage mechanism of SARS CoV Mpro and chemical modification of the octapeptide

The cleavage mechanism of severe acute respiratory syndrome (SARS) coronavirus main proteinase (M-Pro or 3CL(Pro)) for the octapeptide AVLQSGFR is studied using molecular mechanics (MM) and quantum mechanics (QM). The catalytic dyad His-41 and Cys-145 in the active pocket between domain I and H seem to polarize the pi-electron density of the peptide bond between Gin and Ser in the octapeptide, leading to an increase of positive charge on C(CO) of Gin and negative charge on N(NH) of Ser. The possibility of enhancing the chemical bond between Gin and Ser based on the distorted key theory [Anal. Biochem. 233 (1996) 1] is examined. The scissile peptide bond between Gin and Ser is found to be solidified through hybrid peptide bond by changing the carbonyl group CO of Gin to CH2 or CF2. This leads to a break of the pi-bond system for the peptide bond, making the octapeptide (AVLQSGFR) a distorted key and a potential starting system for the design of anti SARS drugs. (C) 2004 Elsevier Inc. All rights reserved.