The mechanism of SARS‐CoV‐2 spike protein‐mediated perturbations of metabolic pathways and modulation of antcin A, a steroid‐like compound isolated from Taiwanofungus camphoratus, are not studied. Here, we investigated the metabolic alteration by SARS‐CoV‐2 spike protein and the regulatory effect of antcin A on SARS‐CoV‐2 spike protein‐induced metabolic changes in the Phorbol 12‐myristate 13‐acetate (PMA)‐induced human monocytes (THP‐1) using proton nuclear magnetic resonance (1H‐NMR) and MetaboAnalyst 5.0 software. The cytotoxic potential of SARS‐CoV‐2 spike protein, antcin A, and dexamethasone was assessed by MTT assay. The metabolomic perturbations and their relation to human coronaviruses' receptors were evaluated by qPCR. This study indicated that the altered metabolites mediated by SARS‐CoV‐2 protein, such as methionine, phosphoenolpyruvic acid, canadine, glutamine, ethanolamine, and phenylalanine, were significantly reversed by antcin A. In addition, antcin A significantly inhibited SARS‐CoV‐2 spike protein‐mediated up‐regulation of TLR‐4 and ACE2 receptors, while GRP78 inhibition was not statistically significant. This is the first study to use 1H‐NMR to investigate SARS‐CoV‐2 spike protein‐induced metabolomic changes in PMA‐induced THP‐1 cells. Antcin A significantly reversed metabolomic alters while dexamethasone failed to fix them. Therefore, we believe that antcin A could be a potential candidate for therapeutic agents for viral infections related to a metabolic abnormality.
Antcins obtained from the fruiting bodies of Taiwanofungus camphoratus, have been traditionally used to treat infections, whereas their role in the SARS-CoV-2 3-chymotrypsin-like protease (3CLPro) remains unclear. We employed both in vitro and in silico approaches to understand the underlying chemical mechanism comprehensively. Our finding revealed that various antcins (A, B, C, H, I, and M) and non-antcins (citronellol and limonene) exhibited lower toxicity to cells than GC376, along with favorable drug-likeness based MTT assay and ADMET prediction. Molecular docking analysis predicted that antcin-B possessed the lowest binding affinity energy and interacts with key residues such as Glu169, Gln189, His41, Leu141, Asn142, Glu16, and His165 employing hydrophobic interaction, hydrogen bonding, and salt bridge. These interactions were further confirmed by molecular dynamics (MD) simulation, which demonstrated the formation of hydrogen bonds with Asn142 and Gly143 and bridge with Glu166 for approximately 40% and 70% of the simulation time, respectively. Indeed, in vitro, 3CLPro activity analysis supports the above notion that antcin-B significantly (96.39%) inhibits 3CLPro activity, which is highly comparable with a known antiviral drug GC367 (96.72%). Consequently, antcin-B could be considered for developing a potential drug candidate for inhibiting 3CLPro activity, thereby impeding reducing the severity of COVID-19 in patients.
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