Understanding the determinants for substrate recognition, regulation of enzymatic activity and the development of broad-spectrum inhibitors of coronavirus 3-chymotrypsin-like proteases

Coronaviruses include lethal human pathogens like severe acute respiratory syndrome coronavirus (SARS-CoV) and the recently emerged Middle-east respiratory coronavirus (MERS-CoV). Coronavirus also impact global economy by infecting farm animals like pigs (porcine epidemic diarrhea virus, PEDV), cows (bovine coronavirus, BCoV) and poultry (avian infectious bronchitis virus, IBV). Moreover, the global distribution of bats that naturally harbor one or more coronavirus strains heightens the likelihood of emergence of a novel highly pathogenic coronavirus in the near future. To combat infections of existing and emerging coronaviruses, it is important to identify coronavirus drug targets that can be utilized for the development of broad-spectrum anti-coronaviral therapeutics. Viral encoded 3-Chymotrypsin-like protease (3CLpro) is essential for viral polyprotein processing to release non-structural proteins that form the replicase complex machinery for viral genome replication. Due to its indispensable role in coronaviral replication, 3CLpro is an attractive drug target. Moreover, high sequence conservation in the vicinity of active site among 3CLpro proteases from different coronavirus subclasses make them an excellent target for the development of broad-spectrum therapeutics for coronavirus infections. The overarching goal of this project is to investigate enzymatic and structural properties of multiple 3CLpro enzymes encompassing different coronavirus subclasses. Understanding the determinants of structural and functional disparity between different 3CLpro enzymes and the factors regulating these properties will aid in the design of broad-spectrum inhibitors of 3CLpro enzymes. (Abstract shortened by ProQuest.)