Drug Repurposing for the SARS-CoV-2 Papain-Like Protease.

Liu, Wenshe; Cho, Chia-Chuan; Li, Shuhua G; Lalonde, Tyler J; Yang, Kai S; Yu, Ge; Qiao, Yuchen; Xu, Shiqing

As the pathogen of COVID-19, SARS-CoV-2 encodes two essential cysteine proteases that process the pathogen's two large polypeptide products pp1a and pp1ab in the human cell host to form 15 functionally important, mature nonstructural proteins. One of the two enzymes is papain-like protease or PL Pro . It possesses deubiquitination and deISGylation activities that suppress host innate immune responses toward SARS-CoV-2 infection. To repurpose drugs for PL Pro , we experimentally screened libraries of 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PL Pro . Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit strong inhibition of PL Pro at 200 𝜇M. More comprehensive characterizations revealed 7 inhibitors GRL0617, SJB2-043, TCID, DUB-IN-1, DUB-IN-3, PR-619, and S130 with an IC 50 value below 40 𝜇M and four inhibitors GRL0617, SJB2-043, TCID, and PR-619 with an IC 50 value below 10 𝜇M. Among four inhibitors with an IC 50 value below 10 𝜇M, SJB2-043 is the most unique in that it doesn't fully inhibit PL Pro but has a noteworthy IC 50 value of 0.56 𝜇M. SJB2-043 likely binds to an allosteric site of PL Pro to convene its inhibition effect, which needs to be further investigated. As a pilot study, the current work indicates that COVID-19 drug repurposing by targeting PL Pro holds promise but in-depth analysis of repurposed drugs is necessary to avoid omitting critical allosteric inhibitors.