Old drugs, new tricks: leveraging known compounds to disrupt coronavirus-induced cytokine storm

Abstract

A major complication in COVID-19 infection consists in the onset of acute respiratory distress fueled by a dysregulation of the host immune network that leads to a run-away cytokine storm. Here, we present an in silico approach that captures the host immune system’s complex regulatory dynamics, allowing us to identify and rank candidate drugs and drug pairs that engage with minimal subsets of immune mediators such that their downstream interactions effectively disrupt the signaling cascades driving cytokine storm. Drug–target regulatory interactions are extracted from peer-reviewed literature using automated text-mining for over 5000 compounds associated with COVID-induced cytokine storm and elements of the underlying biology. The targets and mode of action of each compound, as well as combinations of compounds, were scored against their functional alignment with sets of competing model-predicted optimal intervention strategies, as well as the availability of like-acting compounds and known off-target effects. Top-ranking individual compounds identified included a number of known immune suppressors such as calcineurin and mTOR inhibitors as well as compounds less frequently associated for their immune-modulatory effects, including antimicrobials, statins, and cholinergic agonists. Pairwise combinations of drugs targeting distinct biological pathways tended to perform significantly better than single drugs with dexamethasone emerging as a frequent high-ranking companion. While these predicted drug combinations aim to disrupt COVID-induced acute respiratory distress syndrome, the approach itself can be applied more broadly to other diseases and may provide a standard tool for drug discovery initiatives in evaluating alternative targets and repurposing approved drugs.

Prospects of Novel and Repurposed Immunomodulatory Drugs against Acute Respiratory Distress Syndrome (ARDS) Associated with COVID-19 Disease

“…The basis of the study was the process of defining gene circuits (gene regulatory networks) that are robustly linked with the cytokine storm associated with the COVID-19 disease and, although incited by the virus, can remain activated long after viral clearance. Based on the defined circuits, key targets were chosen before screening and ranking of potential drug candidates [106].…”

Hexahydropyrrolo-[2,3-b]-indole Containing Alkaloids as a SARS-CoV-2 Inhibitors: An Integrated Multi-Target Based in-silico Approach

“…(Brogi, Ramalho, Kuca, Medina-Franco, & Valko, 2020;Ekins, Mestres, & Testa, 2007;Shaker, Ahmad, Lee, Jung, & Na, 2021) The discovery and repurposing of multiple therapeutics to fight against SARS-CoV-2 in a very short period is it's great evidence to overcome the epidemic to a great extent. (Richman et al, 2022;Riva et al, 2020;von Delft et al, 2023) Since the rapid progression of the COVID-19 epidemic, a large number of studies and clinical trials are being performed around the globe. However, there have been a very limited number of drugs were identified which may act effectively against the novel coronavirus.…”