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Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment.
Caruso, Francesco; Pedersen, Jens Z; Incerpi, Sandra; Kaur, Sarjit; Belli, Stuart; Florea, Radu-Mihai; Rossi, Miriam.
  • Caruso F; Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA.
  • Pedersen JZ; Department of Biology, University Tor Vergata, 00133 Rome, Italy.
  • Incerpi S; Department of Sciences, University Roma Tre, 00146 Rome, Italy.
  • Kaur S; Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA.
  • Belli S; Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA.
  • Florea RM; Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA.
  • Rossi M; Department of Chemistry, Vassar College, Poughkeepsie, NY 12604, USA.
Int J Mol Sci ; 23(3)2022 Feb 06.
Article in English | MEDLINE | ID: covidwho-1674672
ABSTRACT
The inflammatory protease caspase-1 is associated with the release of cytokines. An excessive number of cytokines (a "cytokine storm") is a dangerous consequence of COVID-19 infection and has been indicated as being among the causes of death by COVID-19. The anti-inflammatory drug colchicine (which is reported in the literature to be a caspase-1 inhibitor) and the corticosteroid drugs, dexamethasone and methylprednisolone, are among the most effective active compounds for COVID-19 treatment. The SERM raloxifene has also been used as a repurposed drug in COVID-19 therapy. In this study, inhibition of caspase-1 by these four compounds was analyzed using computational methods. Our aim was to see if the inhibition of caspase-1, an important biomolecule in the inflammatory response that triggers cytokine release, could shed light on how these drugs help to alleviate excessive cytokine production. We also measured the antioxidant activities of dexamethasone and colchicine when scavenging the superoxide radical using cyclic voltammetry methods. The experimental findings are associated with caspase-1 active site affinity towards these compounds. In evaluating our computational and experimental results, we here formulate a mechanism for caspase-1 inhibition by these drugs, which involves the active site amino acid Cys285 residue and is mediated by a transfer of protons, involving His237 and Ser339. It is proposed that the molecular moiety targeted by all of these drugs is a carbonyl group which establishes a S(Cys285)-C(carbonyl) covalent bond.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Caspase 1 / Caspase Inhibitors / Coronavirus 3C Proteases / COVID-19 Drug Treatment / Anti-Inflammatory Agents Type of study: Experimental Studies Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23031849

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Caspase 1 / Caspase Inhibitors / Coronavirus 3C Proteases / COVID-19 Drug Treatment / Anti-Inflammatory Agents Type of study: Experimental Studies Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23031849