Abstract
We describe the potential anti coronavirus disease 2019 (COVID-19) action of the methide quinone inhibitor, celastrol. The related methide quinone dexamethasone is, so far, among COVID-19 medications perhaps the most effective drug for patients with severe symptoms. We observe a parallel redox biology behavior between the antioxidant action of celastrol when scavenging the superoxide radical, and the adduct formation of celastrol with the main COVID-19 protease. The related molecular mechanism is envisioned using molecular mechanics and dynamics calculations. It proposes a covalent bond between the S(Cys145) amino acid thiolate and the celastrol A ring, assisted by proton transfers by His164 and His41 amino acids, and a π interaction from Met49 to the celastrol B ring. Specifically, celastrol possesses two moieties that are able to independently scavenge the superoxide radical: the carboxylic framework located at ring E, and the methide-quinone ring A. The latter captures the superoxide electron, releasing molecular oxygen, and is the feature of interest that correlates with the mechanism of COVID-19 inhibition. This unusual scavenging of the superoxide radical is described using density functional theory (DFT) methods, and is supported experimentally by cyclic voltammetry and X-ray diffraction.
Highlights
Human use of plants as sources of medicinal benefit predates written history, and there is a growing interest in traditional plant-based medicines
Celastrol is a methide quinone triterpene isolated from the roots of Tripterygium wilfordii, or “God of Thunder” vine
(5) Celastrol promotes proteotoxic stress, supported by the induction of heat-shock proteins, HSP72, through a thiol-dependent mechanism; these findings imply that celastrol targets proteostasis by disrupting sulfyhydryl homeostasis in human glioblastoma cells [23]
Summary
Human use of plants as sources of medicinal benefit predates written history, and there is a growing interest in traditional plant-based medicines. (6) In addition, it was seen that celastrol reduced lipopolysaccharides (LPS)-induced expression of inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12, and IL-1β These inhibitory effects of celastrol on LPS were reversed by thiol donors (N-acetyl-L-cysteine and dithiothreitol), suggesting that the thiol reactivity of celastrol contributes to its inhibitory effects on macrophages. Our described quinone embelin inhibition mechanism on 3CLpro implicates Cys145 assisted through H-bonds from nearby amino acids, and strongly resembles the mechanism of embelin antioxidant activity toward the superoxide radical [34,35]. Both of these two chemical reactions underscore quinone electron affinity. We describe the mechanism of celastrol, Scheme 1, at the active site of the main COVID-19 protease, 3CLpro, using crystal structure, electrovoltaic antioxidant measurements, docking, and density functional theory (DFT) methods
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