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Drug Repurposing for the SARS‐CoV‐2 Papain‐Like Protease
Author(s) -
Cho ChiaChuan,
Li Shuhua G.,
Lalonde Tyler J.,
Yang Kai S.,
Yu Ge,
Qiao Yuchen,
Xu Shiqing,
Ray Liu Wenshe
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100455
Subject(s) - drug repositioning , protease , covid-19 , papain , drug , repurposing , virology , drug discovery , pharmacology , chemistry , computational biology , medicine , biology , enzyme , biochemistry , ecology , disease , pathology , outbreak , infectious disease (medical specialty)
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 seven 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 does not 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.