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.
Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19 Drug Treatment , Caspase 1/drug effects , Caspase Inhibitors/pharmacology , Coronavirus 3C Proteases/drug effects , Anti-Inflammatory Agents/chemistry , COVID-19/metabolism , Caspase 1/chemistry , Caspase 1/metabolism , Caspase Inhibitors/chemistry , Colchicine/chemistry , Colchicine/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Dexamethasone/pharmacology , Humans , Models, Molecular , Molecular Docking Simulation , Pentacyclic Triterpenes/pharmacology , Protein Interaction Domains and Motifs , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , Viral Protease Inhibitors/chemistry , Viral Protease Inhibitors/pharmacologyABSTRACT
BACKGROUND: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. METHODS: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. RESULTS: Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2's main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. CONCLUSIONS: Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.
Subject(s)
Antiviral Agents/pharmacology , Atorvastatin/pharmacology , COVID-19 Drug Treatment , Lung/drug effects , Organoids/drug effects , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Atorvastatin/chemistry , COVID-19/prevention & control , Cell Line , Coronavirus 3C Proteases/chemistry , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Doxycycline/pharmacology , Drug Approval , Drug Repositioning , Gene Expression Regulation/drug effects , Humans , Lung/virology , Models, Biological , Molecular Docking Simulation , Organoids/virology , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Trifluoperazine/chemistry , Trifluoperazine/pharmacology , United States , United States Food and Drug Administration , Vesiculovirus/genetics , Virus Internalization/drug effectsABSTRACT
Covid-19 urges a deeper understanding of the underlying molecular mechanisms involved in illness progression to provide a prompt therapeutical response with an adequate use of available drugs, including drug repurposing. Recently, it was suggested that a dysregulated bradykinin signaling can trigger the cytokine storm observed in patients with severe Covid-19. In the scope of a drug repurposing campaign undertaken to identify bradykinin antagonists, raloxifene was identified as prospective compound in a virtual screening process. The pharmacodynamics profile of raloxifene towards bradykinin receptors is reported in the present work, showing a weak selective partial agonist profile at the B2 receptor. In view of this new profile, its possible use as a therapeutical agent for the treatment of severe Covid-19 is discussed.