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Drug Repurposing for the SARS-CoV-2 Papain-Like Protease.
Cho, Chia-Chuan; Li, Shuhua G; Lalonde, Tyler J; Yang, Kai S; Yu, Ge; Qiao, Yuchen; Xu, Shiqing; Ray Liu, Wenshe.
  • Cho CC; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Li SG; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Lalonde TJ; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Yang KS; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Yu G; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Qiao Y; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Xu S; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
  • Ray Liu W; The Texas A&M Drug Discovery Laboratory Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
ChemMedChem ; 17(1): e202100455, 2022 01 05.
Article in English | MEDLINE | ID: covidwho-1366225
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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ABSTRACT
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 PLPro . It possesses deubiquitination and deISGylation activities that suppress host innate immune responses toward SARS-CoV-2 infection. To repurpose drugs for PLPro , we experimentally screened libraries of 33 deubiquitinase and 37 cysteine protease inhibitors on their inhibition of PLPro . Our results showed that 15 deubiquitinase and 1 cysteine protease inhibitors exhibit strong inhibition of PLPro 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 IC50 value below 40 µM and four inhibitors GRL0617, SJB2-043, TCID, and PR-619 with an IC50 value below 10 µM. Among four inhibitors with an IC50 value below 10 µM, SJB2-043 is the most unique in that it does not fully inhibit PLPro but has a noteworthy IC50 value of 0.56 µM. SJB2-043 likely binds to an allosteric site of PLPro 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 PLPro holds promise, but in-depth analysis of repurposed drugs is necessary to avoid omitting critical allosteric inhibitors.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Drug Repositioning / Coronavirus Papain-Like Proteases / SARS-CoV-2 Limits: Humans Language: English Journal: ChemMedChem Journal subject: Pharmacology / Chemistry Year: 2022 Document Type: Article Affiliation country: Cmdc.202100455

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Cysteine Proteinase Inhibitors / Drug Repositioning / Coronavirus Papain-Like Proteases / SARS-CoV-2 Limits: Humans Language: English Journal: ChemMedChem Journal subject: Pharmacology / Chemistry Year: 2022 Document Type: Article Affiliation country: Cmdc.202100455