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

Francesco Caruso,Radu-Mihai Florea,Miriam Rossi,Stuart Belli,Sarjit Kaur,Sandra Incerpi,Jens Z Pedersen

doi:10.3390/ijms23031849

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.

Highlights

The mechanism of COVID-19 development remains unclear, unregulated cytokine release resulting in an excessive inflammatory response is likely implicated
Using molecular mechanics docking techniques, this study shows that four wellknown anti-inflammatory drugs, which all have activity against COVID-19, show inhibitory effects on caspase-1
Since the human enzyme is associated with triggering a potentially lethal cytokine storm, released by the immune system during COVID-19 infection, our results help to explain why these four inhibitory drugs are useful for the treatment of COVID-19 illness

Summary

Introduction

The mechanism of COVID-19 development remains unclear, unregulated cytokine release resulting in an excessive inflammatory response is likely implicated. “Cytokine storm” and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions and monogenic disorders [3]. These damaging conditions prompt the formation of inflammasomes, large multi-protein complexes that include the protease caspase-1. D, which triggers pyroptosis, a pro-inflammatory form of cell death These are likely implicated in acute COVID-19 pathogenesis and may be more damaging to the host than the response associated with viral-induced cell death in the host [4].

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