Along with the Mpro, papain‐like protease (PLpro) also cleaves polyproteins which is an important process for viral replication. PLpro cleaves at the first three positions creating three nonstructural functional proteins (nsp1‐nsp3). In particular, nsp3 is central for the generation of the viral replication complex. The multifunctionality of PLpro in deubiquitinating, de‐ISGylation (ISG: interferon‐stimulated gene), 195 ,  196  and in the evasion of the innate immune response make PLpro an attractive antiviral drug target.