PLpro Inhibitor Design

Due to the complex nature of SARS-CoV replication, a number of processes are considered essential to the coronaviral lifecycle and therefore provide a significant number of targets for inhibiting viral replication.  An early and essential process is the cleavage of a multidomain, viral polyprotein into 16 mature components termed non-structural proteins (nsp’s), which assemble into complexes to execute viral RNA synthesis.  Two cysteine proteases that reside within the polyprotein, a papain-like protease (PLpro) and a 3C-like protease (3CLpro), catalyze their own release and that of the other nsp’s from the polyprotein, thereby initiating virus-mediated RNA replication.  Despite numerous biochemical, structural and inhibitor-development studies directed at 3CLpro, potent antivirals that directly target 3CLpro have yet to be developed.  In contrast, structural and functional studies directed at PLpro are far less numerous but have established important roles for PLpro beyond viral peptide cleavage including deubiquitination, deISGylation, and involvement in virus evasion of the innate immune response.  Recent studies have also shown that an enzyme homologous to PLpro from the human coronavirus 229E, PLP2, is essential for viral replication.  The following paper reports our initial design approach for PLpro inhibitors, shown schematically above.

K. Ratia, S. Pegan, J. Takayama, K. Sleeman, M. Coughlin, S. Baliji, R. Chaudhuri, W. Fu, B.S. Prabhakar, M.E. Johnson, S.C. Baker, A.K. Ghosh, and Andrew D. Mesecar (2008) “A new class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication,” Proceedings of the National Academy of Sciences, USA, 105(42), 16119-16124. (Abstract)