Mitoquinone mesylate targets SARS-CoV-2 and associated lung inflammation through host pathways

Petcherski, A.; Sharma, M.; Daskou, M.; Satta, S.; Vasilopoulos, H.; Hugo, C.; Ritou, E.; Dillon, B. J.; Fung, E.; Garcia, G.; Scafoglio, C.; Purkayastha, A.; Gomperts, B.; Fishbein, G. A.; Arumugaswami, V.; Liesa, M.; Shirihai, O. S.; Kelesidis, T.

doi:10.1101/2022.02.22.481100

bioRxiv · 10.1101/2022.02.22.481100

Mitoquinone mesylate targets SARS-CoV-2 and associated lung inflammation through host pathways

Petcherski, A.·Sharma, M.·Daskou, M.·Satta, S.·Vasilopoulos, H.·Hugo, C.·Ritou, E.·Dillon, B. J.·Fung, E.·Garcia, G.·Scafoglio, C.·Purkayastha, A.·Gomperts, B.·Fishbein, G. A.·Arumugaswami, V.·Liesa, M.·Shirihai, O. S.·Kelesidis, T.

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Abstract

To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern in vitro and in vivo. Mito-MES had nanomolar in vitro antiviral potency against the Beta and Delta SARS-CoV-2 variants as well as the murine hepatitis virus (MHV-A59). Mito-MES given in SARS-CoV-2 infected K18-hACE2 mice through oral gavage reduced viral titer by nearly 4 log units relative to the vehicle group. We found in vitro that the antiviral effect of Mito-MES is attributable to its hydrophobic dTPP+ moiety and its combined effects scavenging reactive oxygen species (ROS), activating Nrf2 and increasing the host defense proteins TOM70 and MX1. Mito-MES was efficacious reducing increase in cleaved caspase-3 and inflammation induced by SARS-CoV2 infection both in lung epithelial cells and a transgenic mouse model of COVID-19. Mito-MES reduced production of IL-6 by SARS-CoV-2 infected epithelial cells through its antioxidant properties (Nrf2 agonist, coenzyme Q10 moiety) and the dTPP moiety. Given established safety of Mito-MES in humans, our results suggest that Mito-MES may represent a rapidly applicable therapeutic strategy that can be added in the therapeutic arsenal against COVID-19. Its potential long-term use by humans as diet supplement could help control the SARS-CoV-2 pandemic, especially in the setting of rapidly emerging SARS-CoV-2 variants that may compromise vaccine efficacy. One-Sentence SummaryMitoquinone/mitoquinol mesylate has potent antiviral and anti-inflammatory activity in preclinical models of SARS-CoV-2 infection.

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Petcherski, A., Sharma, M., Daskou, M., Satta, S., Vasilopoulos, H., Hugo, C., Ritou, E., Dillon, B. J., Fung, E., Garcia, G., Scafoglio, C., Purkayastha, A., Gomperts, B., Fishbein, G. A., Arumugaswami, V., Liesa, M., Shirihai, O. S., Kelesidis, T.. 2022-02-25. Mitoquinone mesylate targets SARS-CoV-2 and associated lung inflammation through host pathways. https://doi.org/10.1101/2022.02.22.481100

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