Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates

Abstract

Lack of efficiency has been a major problem shared by all currently developed anti-SARS-CoV-2 therapies. Our previous study shows that SARS-CoV-2 structural envelope (2-E) protein forms a type of cation channel, and heterogeneously expression of 2-E channels causes host cell death. In this study we developed a cell-based high throughput screening (HTS) assay and used it to discover inhibitors against 2-E channels. Among 4376 compounds tested, 34 hits with cell protection activity were found. Followed by an anti-viral analysis, 15 compounds which could inhibit SARS-CoV-2 replication were identified. In electrophysiological experiments, three representatives showing inhibitory effect on 2-E channels were chosen for further characterization. Among them, proanthocyanidins directly bound to 2-E channel with binding affinity (KD) of 22.14 μM in surface plasmon resonance assay. Molecular modeling and docking analysis revealed that proanthocyanidins inserted into the pore of 2-E N-terminal vestibule acting as a channel blocker. Consistently, mutations of Glu 8 and Asn 15, two residues lining the proposed binding pocket, abolished the inhibitory effects of proanthocyanidins. The natural product proanthocyanidins are widely used as cosmetic, suggesting a potential of proanthocyanidins as disinfectant for external use. This study further demonstrates that 2-E channel is an effective antiviral drug target and provides a potential antiviral candidate against SARS-CoV-2.

Non-Woven Infection Prevention Fabrics Coated with Biobased Cranberry Extracts Inactivate Enveloped Viruses Such as SARS-CoV-2 and Multidrug-Resistant Bacteria

“…Cranberry extracts are well known for their pharmacological potential [ 42 , 43 , 44 , 45 ]. Furthermore, the natural product proanthocyanidins present in the cranberry extracts are widely used as cosmetic, suggesting a potential use as disinfectant for external use [ 46 ]. Su et al showed the antiviral activity of the cranberry juice and PACs against different virus, including human enteric virus surrogates, murine norovirus, feline calicivirus, bacteriophage MS2 (ssRNA), and bacteriophage phiX-174 (ssDNA) [ 47 ].…”

“…The PACs could act by binding and destroying the viral capsid structure or could cause inhibition of key enzymes involved in viral replication [ 49 ]. A recent study on the discovery of SARS-CoV-2 channel inhibitors as antiviral candidates, has shown that PACs directly bound to 2-E channel with binding affinity (KD) of 22.14 μM in surface plasmon resonance assay [ 46 ]. In addition, some studies have shown that PACs exposure prevents some bacteriophages from attaching to their bacterial host [ 50 ].…”

Effectiveness of Natural Antioxidants against SARS-CoV-2? Insights from the In-Silico World

“…Glycyrrhizin, Glycyrrhetinic acid, and Baicalin have also shown binding to E-channel protein. Proanthocyanidins have been reported to inhibit the MPro and E-channel protein of the SARS-CoV-2 [ 104 ].…”

Does Oxidative Stress Management Help Alleviation of COVID-19 Symptoms in Patients Experiencing Diabetes?

“…Quercetin, apigenin, baicalin, luteolin, hesperidin, genistein, proanthocyanidin and eriodictyol have been found to be capable of alleviating oxidative stress in diabetic nephropathy [63]. Incidentally, all the above flavonoid compounds have been reported to bind to SARS-CoV-2 protein components or the receptor hACE2 [54][55][56][64][65][66][67][68][69]. These flavonoids are also antioxidants suggesting a common mode of action in both COVID-19 and diabetes, which in all probability is through reducing oxidative stress.…”