Only Dual Anti-Inflammatory/Antiviral Medication in Development to Treat COVID-19 Shows Promise in Study

(Miami, FL, USA) was originally designed to disrupt cell signaling in a variety of cancers and uses that same mechanism of action to dampen the cytokine storm that leads to severe acute respiratory distress syndrome (SARDS) in the most serious cases of COVID-19. VERU-111 is an orally bioavailable bis-indole that binds to the “colchicine binding site” of a and b tubulin and inhibits tubulin polymerization at low nanomolar concentrations. VERU-111 disrupts the microtubule filaments similar to nocodazole and colchicine, the central mechanism that contributes to both their antiviral and anti-inflammatory activities.

The central mechanism of colchicine clinical anti-inflammatory and anti-viral activities is based on its ability to bind the “colchicine binding” sites on alpha and beta tubulin which when incorporated into microtubule block subsequent microtubule polymerization. Inhibition of tubulin polymerization is responsible for the effects of colchicine on cell migration, cytokine release, and intracellular trafficking (antiviral) and disruption of inflammatory cell activities. Colchicine modulates leucocyte mediated inflammatory activities including inhibition of leucocyte production of superoxides and release of various cytokines and pyrogens. Colchicine-like agents may, therefore, be useful in treating the “cytokine storm” seen with SARS-CoV 2.

Based on its mechanistic similarities to other microtubule depolymerizing agents as well as its preclinical and clinical efficacy and safety experience, VERU-111 may have a two-pronged approach to the treatment of SARS-CoV-2: antiviral and anti-inflammatory agent. As an antiviral, it may have direct effects on S protein-microtubule trafficking with the potential to reduce the production of infectious virions particularly by affecting viral replication and assembly and virion egress. As an anti-inflammatory agent, it may reduce virally induced severe inflammation in the respiratory system and may reduce the incidence of cytokine storm and septic shock that can occur in patients that progress to severe acute respiratory pneumonia.

The just-completed in vitro study has found that VERU-111 is comparable to or better than the steroid dexamethasone, which “decreases inflammation, but has no antiviral activity. In the study, the researchers took a mouse spleen and shocked it with endotoxin to create a cytokine storm. Then they treated the tissue using the same VERU-111 concentrations that would be used in humans, and measured the drug’s anti-inflammatory activity. The researchers found a reduction of 123% in concentrations of IL-1, 85% in IL-6 and 96% in IL-8. These are the key cytokines involved in the cytokine storms triggered by severe SARS-CoV-2 infections in humans.

“Viruses are macromolecules. To block replication, you have to hijack the cell replication machinery. Otherwise, the virus enters the cells, hops onto the microtubules which, like a taxicab, bring the viral RNA to the nucleus for replication, where the virions assemble into new virus particles, which hop back to the microtubules to exit the cell,” Mitchell Steiner, M.D., CEO, told BioSpace. That mechanism of action is well known. “What’s new is that we have a more potent, safer molecule. VERU-111 targets microtubules – the transportation system within the cell.”

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