Calming the (Cytokine) Storm: Dimethyl Fumarate as a Therapeutic Candidate for COVID-19

Abstract

COVID-19 has rapidly spread worldwide and incidences of hospitalisation from respiratory distress are significant. While a vaccine is in the pipeline, there is urgency for therapeutic options to address the immune dysregulation, hyperinflammation and oxidative stress that can lead to death. Given the shared pathogenesis of severe cases of COVID-19 with aspects of multiple sclerosis and psoriasis, we propose dimethyl fumarate as a viable treatment option. Currently approved for multiple sclerosis and psoriasis, dimethyl fumarate is an immunomodulatory, anti-inflammatory and anti-oxidative drug that could be rapidly implemented into the clinic to calm the cytokine storm which drives severe COVID-19.

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…The methyl ester of fumaric acid (dimethylfumarate, DMF), which is already in use for the treatment of psoriasis and multiple sclerosis, is a potent activator of Nrf2. Since both these diseases share with COVID-19 an inflammatory basis, this drug has been indicated as a potential therapeutic candidate [ 160 , 161 ]. From a molecular point of view, DMF has been shown to inhibit virus entry by inducing anti-protease protein SPLI expression and inhibiting transmembrane serine protease TRMPSS2, a cell surface receptor, required for SARS-CoV-2 entry to target host cells [ 162 ].…”

“…Another Nrf2 activator is 4-octyl itaconate, an analogous of itaconate with immunoregulatory and antioxidative effects produced by decarboxylating cis-aconitate. This compound seems quite promising since it showed suppression of inflammatory response in COVID-19 [ 161 ]. Other potential drugs are sulforaphane, isolated from broccoli, and its encapsulated variant sulfodarex with demonstrated anti-inflammatory response in lungs, acting as NADPH:quinone oxidoreductase 1 inducer [ 165 ].…”

Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

“…Although developed recently, IRAK4 inhibitors are under assessment in psoriasis, whilst in rheumatoid arthritis a completed phase II clinical trial has demonstrated clinical improvement (142). Interestingly, dimethyl fumarate, already of proven clinical efficacy in treating both multiple sclerosis and psoriasis, is not only a direct inhibitor of IRAK4 but also suppresses innate proinflammatory cytokines in pDCs, providing a strong mechanistic rationale for its recently proposed repurposing for COVID-19 "cytokine storm" (143,144). Lowgrade inflammation is common in autoimmunity (145), with an inflammatory signature similar to COVID-19 (146).…”

Science's Response to CoVID‐19

“…Oxidative stress is an important contributing factor to serious CoVID‐19 cases and there are reports that CoVID‐19 infection may suppress cellular antioxidant response [297] . In these respects, there has been proposed to be a link between multiple sclerosis (MS) and severe CoVID‐19 pathologies [32] . One interesting hypothesis to arise from this, albeit slightly tenuous, link is that dimethylfumarate (DMF; Tecfidera), a drug approved to treat relapsing MS, may be active against CoVID (Figure 5).…”

“…Consistent with these observations, viral proteins bind host proteins abundant in the lungs. Many other reported CoVID‐19‐associated pathologies are associated with the immune response and blood clotting: cytokine storms leading to hyperinflammation (elevated inflammatory markers including ferritin, interleukins 1 and 6, and C‐reactive protein have been reported); [30] oxidative stress, potentially leading to ferroptosis in several tissues; [31] changes [32] in immune cells; [33] thrombic microangiopathy (blood clots forming in capillaries and arterioles); [34] and a host of other issues, including neurological problems [35] . Immune evasion is one of the hallmarks separating CoVID‐19 from SARS‐CoV, although how these observations link to the clinical outcomes is unclear.…”