Mitoquinone mesylate targets SARS-CoV-2 infection in preclinical models

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.

SARS-CoV-2 infection alters mitochondrial and cytoskeletal function in human respiratory epithelial cells mediated by expression of spike protein

“…Specifically, the Spike infection significantly decreased basal respiration (0.52-fold in Spike vs VSV-G, P = 0.0034) ( Fig. 5D ), which was similar to the effect of SCV2 infection in Calu3 cells as compared to the uninfected cells ( 29 ). Particularly, maximal respiration (0.5-fold in Spike vs VSV-G, P = 0.0032) ( Fig.…”

MitoQ Alleviated PM2.5 Induced Pulmonary Epithelial Cells Injury by Inhibiting Mitochondrial-Mediated Apoptosis

“…After administration of oral supplementation with MitoQ the patients with impaired endothelial function improved brachial artery flow-mediated dilation, aortic stiffness, and plasma oxidized low-density lipoprotein ( 37 , 38 ). A preprint study showed MitoQ and mitoquinol mesylate could play an anti-inflammatory and antiviral role through its mitochondrial antioxidant properties ( 39 ). Although MitoQ can reduce pulmonary damage in vitro and in vivo, but the clinical trials showing that MitoQ treats or protects the pulmonary disease are still lacking ( 26 – 29 ).…”

Possible Pathogenesis and Prevention of Long COVID: SARS-CoV-2-Induced Mitochondrial Disorder

“…Mitochondrial oxidative stress can also be reduced using mitochondrion-targeted catalytic antioxidants such as MnTBAP [188], EUK-8, and EUK-134 [189], as well as Mito-TEMPO and mitoquinol [112,162,190]. In addition, mitochondrial quinone/mitochondrial phenol mesylate (Mito-MES) has been demonstrated to possess significant antiviral activity against SARS-CoV-2 and can reduce excessive inflammation in the host [191]. Effective treatment can also be obtained with mPTP inhibitors such as NIM811 [192,193].…”