Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment.
Francesco CarusoJens Zacho PedersenSandra IncerpiSarjit KaurStuart BelliRadu-Mihai FloreaMiriam RossiPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- cell death
- coronavirus disease
- induced apoptosis
- sars cov
- inflammatory response
- anti inflammatory
- oxidative stress
- amino acid
- low dose
- systematic review
- drug induced
- endoplasmic reticulum stress
- weight gain
- signaling pathway
- emergency department
- respiratory syndrome coronavirus
- cancer therapy
- stem cells
- physical activity
- toll like receptor
- body mass index
- hydrogen peroxide
- weight loss
- cell therapy
- lps induced
- electron transfer