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 . It possesses deubiquitination and deISGylation activities that suppress host innate immune responses toward SARS-CoV-2 infection. To repurpose drugs for PL , we experimentally screened libraries of 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PL . Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit strong inhibition of PL at 200?μM. More comprehensive... More
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 . It possesses deubiquitination and deISGylation activities that suppress host innate immune responses toward SARS-CoV-2 infection. To repurpose drugs for PL , we experimentally screened libraries of 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PL . Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit strong inhibition of PL at 200?μM. More comprehensive characterizations revealed seven inhibitors GRL0617, SJB2-043, TCID, DUB-IN-1, DUB-IN-3, PR-619, and S130 with an IC value below 40 μM and four inhibitors GRL0617, SJB2-043, TCID, and PR-619 with an IC value below 10 μM. Among four inhibitors with an IC value below 10 μM, SJB2-043 is the most unique in that it does not fully inhibit PL but has a noteworthy IC value of 0.56 μM. SJB2-043 likely binds to an allosteric site of PL 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 holds promise, but in-depth analysis of repurposed drugs is necessary to avoid omitting critical allosteric inhibitors.
