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Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment

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...

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Autores principales: Caruso, Francesco, Pedersen, Jens Z., Incerpi, Sandra, Kaur, Sarjit, Belli, Stuart, Florea, Radu-Mihai, Rossi, Miriam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837144/
https://www.ncbi.nlm.nih.gov/pubmed/35163769
http://dx.doi.org/10.3390/ijms23031849
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author Caruso, Francesco
Pedersen, Jens Z.
Incerpi, Sandra
Kaur, Sarjit
Belli, Stuart
Florea, Radu-Mihai
Rossi, Miriam
author_facet Caruso, Francesco
Pedersen, Jens Z.
Incerpi, Sandra
Kaur, Sarjit
Belli, Stuart
Florea, Radu-Mihai
Rossi, Miriam
author_sort Caruso, Francesco
collection PubMed
description 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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spelling pubmed-88371442022-02-12 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 Int J Mol Sci Article 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. MDPI 2022-02-06 /pmc/articles/PMC8837144/ /pubmed/35163769 http://dx.doi.org/10.3390/ijms23031849 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Caruso, Francesco
Pedersen, Jens Z.
Incerpi, Sandra
Kaur, Sarjit
Belli, Stuart
Florea, Radu-Mihai
Rossi, Miriam
Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment
title Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment
title_full Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment
title_fullStr Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment
title_full_unstemmed Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment
title_short Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment
title_sort mechanism of caspase-1 inhibition by four anti-inflammatory drugs used in covid-19 treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8837144/
https://www.ncbi.nlm.nih.gov/pubmed/35163769
http://dx.doi.org/10.3390/ijms23031849
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