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.
Highlights
As the SARS-CoV-2 pandemic unfolds across the globe, more than 100 million people have been diagnosed and 3 million deaths have been reported worldwide
Drugs that target host cells, such as dexamethasone, hydroxychloroquine, and chloroquine have been used for the treatment of COVID-19 perhaps through enhancing the innate immune system and attenuating the inflammatory response [20,21,22]
We found that the 2 structural envelope (2-E) channel inhibitors are able to protect host cells from damage and exhibit anti-SARSCoV-2 activity, suggesting a possibility of identifying antiviral hits through evaluating cell-protective efficiency of compounds
Summary
As the SARS-CoV-2 pandemic unfolds across the globe, more than 100 million people have been diagnosed and 3 million deaths have been reported worldwide. One targets SARS-CoV-2 itself and the other acts on the host immune system or host cell [6, 7]. Some traditional Chinese medicines such as Lianhuaqingwen, were reported to reduce viral replication and improve the clinical symptoms of COVID-19 through its high inhibitory effect on human angiotensin-converting enzyme 2 (hACE2) [17,18,19]. Drugs that target host cells, such as dexamethasone, hydroxychloroquine, and chloroquine have been used for the treatment of COVID-19 perhaps through enhancing the innate immune system and attenuating the inflammatory response [20,21,22]. Though many potential drugs partly have anticoronavirus effects in animal infection models and have been evaluated in ongoing clinical trials, there is no specific drug for COVID-19 currently. Dexamethasone only modestly reduces mortality of patients who Received: 23 February 2021 Accepted: 29 June 2021
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