Papain-like proteases (PLPro) are hydrolytic enzymes which cleave peptidic bonds using a Cys:His catalytic dyad. Both polyproteins encoded by the coronavirus genome contain a shared papain-like domain, which plays a key role in their maturation by cleaving non-strutural proteins (nsp) 1, 2 and 3 from the polyproteins . In SARS-CoV and SARS-CoV2 ,this papain-like protease additionally has significant deubiquinating activity, and targets either ubiquitin chains (in SARS-CoV) or the host's interferon-stimulated gene 15 protein (ISG15). Due to the limited conservation of ISG15 sequences in different species, SARS-CoV2 PLPro is not equally active towards ISG15 from different species: a 500-fold excess of sheep and vesper bat ISG15 is completely cleaved in 30minutes, ISG15 from fish is immune to cleavage, and the same 500-fold excess of human, pig or camel ISG15 is almost completely cleaved in 60 minutes . Cleavage of ISG15 decreases interferon response and, accordingly, inihibition of SARS-CoV2 PLPro has been shown to increase the levels of interferon pathway markers in infected cells, in addition to its expected role in decreasing viral replication . Inhibition of PLPro therefore appears to be an attractive strategy to decrease SARS-CoV2 proliferation in infected cells and virus-induced supression of imune responses.