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

Abstract

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 II seem to polarize the pi-electron density of the peptide bond between Gln and Ser in the octapeptide, leading to an increase of positive charge on C(CO) of Gln and negative charge on N(NH) of Ser. The possibility of enhancing the chemical bond between Gln and Ser based on the "distorted key" theory [Anal. Biochem. 233 (1996) 1] is examined. The scissile peptide bond between Gln and Ser is found to be solidified through "hybrid peptide bond" by changing the carbonyl group CO of Gln to CH(2) or CF(2). 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.

Isolation and Characterization of a Trypsin-Chymotrypsin Inhibitor from the Seeds of Green Lentil (Lens culinaris)

“…Protease inhibitors and their selectivity have formed a topic of intense investigations [such as inhibitors of caspases (cysteinyl aspartate-specific proteases) for finding drugs to treat neurodegenerative diseases, ischemic injury and cancer [1][2][3]; BACE1, BACE2, and cathepsin-E inhibitor for treating Alzheimer Disease [4][5][6][7]; HIV-1 protease inhibitor for treating AIDS [8][9][10][11][12]; coronavirus main protease inhibitor for treating SARS [13][14][15][16][17][18][19] [17,18,[20][21][22][23]. Plants produce several types of protease inhibitors including Bowman-Birk inhibitors Kunitz inhibitors and squash inhibitors [24][25][26][27][28].…”

Pattern Recognition Methods for Protein Functional Site Prediction

“…However, the introduction of the bio-basis function classifiers also posed new difficulties which need further studies. Nevertheless, it is encouraging to note that using the distorted key theory that was originally proposed for finding peptide inhibitors against HIV protease [22,23] has been effectively used to find inhibitors against SARS (severe acute respiratory syndrome) enzyme very recently [101][102][103][104][105].…”

Discovery of Anti-Hiv Drugs Using Computer Aided Drug Designing Tools

“…Actually, the molecule thus modified can be compared to a "distorted key" which can be inserted into a lock but can neither open the lock nor be pulled out from it, spontaneously becoming an ideal competitive inhibitor against the SARS proteinase. Then we did a docking study of their proposed AVLQSGFR octapeptide to the SARS-CoV Mpro based on the three-dimensional structure of SARS coronavirus main proteinase through a homologous approach [9][10][11][12][13]. The binding results show that the octapeptide is bound to the SARS proteinase through six hydrogen bonds.…”