Sticking it to PLpro: using substrate decoys as inhibitors of coronavirus proteases

Abstract

Several viruses, including coronaviruses, are known to code for deubiquitinating enzymes in their genomes. These viral enzymes are called papain-like proteases and are essential for viral replication. Besides this crucial task, these proteases also have immune evasive capabilities through its ability to cleave ubiquitin and ubiquitin-like protein ISG15 from cellular substrates as binding of these molecules to host proteins is often needed to induce an immune response. These roles in viral replication and immune evasion make the protease an attractive viral drug target. Mutated versions of ubiquitin, called ubiquitin variants, were screened for and tested as inhibitors of human and veterinary coronavirus proteases in cell-based assays. Other host-pathogen interactions of the protease were also investigated.