Your browser doesn't support javascript.
SARS-CoV-2 Main Protease Targets Host Selenoproteins and Glutathione Biosynthesis for Knockdown via Proteolysis, Potentially Disrupting the Thioredoxin and Glutaredoxin Redox Cycles.
Gallardo, Ignacio A; Todd, Daniel A; Lima, Stella T; Chekan, Jonathan R; Chiu, Norman H; Taylor, Ethan Will.
  • Gallardo IA; Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27403, USA.
  • Todd DA; Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27403, USA.
  • Lima ST; Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27403, USA.
  • Chekan JR; Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27403, USA.
  • Chiu NH; Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27403, USA.
  • Taylor EW; Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27403, USA.
Antioxidants (Basel) ; 12(3)2023 Feb 23.
Article in English | MEDLINE | ID: covidwho-2259905
ABSTRACT
Associations between dietary selenium status and the clinical outcome of many viral infections, including SARS-CoV-2, are well established. Multiple independent studies have documented a significant inverse correlation between selenium status and the incidence and mortality of COVID-19. At the molecular level, SARS-CoV-2 infection has been shown to decrease the expression of certain selenoproteins, both in vitro and in COVID-19 patients. Using computational methods, our group previously identified a set of six host proteins that contain potential SARS-CoV-2 main protease (Mpro) cleavage sites. Here we show experimentally that Mpro can cleave four of the six predicted target sites, including those from three selenoproteins thioredoxin reductase 1 (TXNRD1), selenoprotein F, and selenoprotein P, as well as the rate-limiting enzyme in glutathione synthesis, glutamate-cysteine ligase catalytic subunit (GCLC). Cleavage was assessed by incubating recombinant SARS-CoV-2 Mpro with synthetic peptides spanning the proposed cleavage sites, and analyzing the products via UPLC-MS. Furthermore, upon incubation of a recombinant Sec498Ser mutant of the full TXNRD1 protein with SARS-CoV-2 Mpro, the predicted cleavage was observed, destroying the TXNRD1 C-terminal redox center. Mechanistically, proteolytic knockdown of both TXNRD1 and GCLC is consistent with a viral strategy to inhibit DNA synthesis, conserving the pool of ribonucleotides for increased virion production. Viral infectivity could also be enhanced by GCLC knockdown, given the ability of glutathione to disrupt the structure of the viral spike protein via disulfide bond reduction. These findings shed new light on the importance of dietary factors like selenium and glutathione in COVID-19 prevention and treatment.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Type of study: Observational study / Prognostic study Language: English Year: 2023 Document Type: Article Affiliation country: Antiox12030559

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Type of study: Observational study / Prognostic study Language: English Year: 2023 Document Type: Article Affiliation country: Antiox12030559