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bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.435959; this version posted March 19, 2021. The copyright holder for this preprint(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It ismade available under aCC-BY-NC-ND 4.0 International license.DiscussionThe development of effective prevention and treatment strategies for SARS-CoV-2 infection isstill at the early stages. Although the first vaccines received now marketing authorization,challenges in distribution concerns or about durable effectiveness, and risk of re-infectionremain (17, 18). Subsequent infections may possibly be milder than the first one, though.Besides vaccination against COVID-19, blocking the accessibility of the virus to membraneboundACE2 as the primary receptor for SARS-CoV-2 target cell entry, represents analternative strategy to prevent COVID-19. Here, different approaches exist (19), but of courseeach of these treatment strategies also has its fundamental as well as translational challengeswhich need to be overcome for clinical utility. Technical hurdles include off-target potential,ACE2-independent effects, stability or toxicity (19). Compounds from natural origin could bean important resource here as they are described long term and many of them have beenestablished as safe. While in silico docking experiments suggested different common naturalcompounds as ACE2 inhibitors, spike binding inhibition to ACE2 has not been shown for mostof them so far, which might be explained by a lack of complete coverage of ACE2 bindingresidues by the compounds (20). However, for glycyrrhizin, nobiletin, and neohesperidin,ACE2 binding falls partially within the RBD contact region and thus, these have been proposedto additionally block spike binding to ACE2 (20). The same accounts for synthetic ACE2inhibitors, such as N-(2-aminoethyl)-1 aziridine-ethanamine (NAAE) (21). In contrast, thelipoglycopeptide antibiotic dalbavancin has now been identified as both, ACE2 binder andSARS-CoV-2 spike-ACE2 inhibitor (22); SARS-CoV-2 infection was effectively inhibited in bothmouse and rhesus macaque models by this compound. Also, for a hydroalcoholicpomegranate peel extract, blocking of spike-ACE2 interaction was shown at 74%, for its mainconstituents punicalagin at 64%, and ellagic acid at 36%. Using SARS-CoV-2 spikepseudotyped lentivirus infection of human kidney-2 (HK-2) cells, virus entry was then efficientlyblocked by the peel extract (23). In the present study, we could show potent ACE2-spike S1RBD protein inhibition by T. officinale extracts using a cell-free assay and confirmed this findingby demonstrating efficient ACE2 cell surface binding inhibition in two human cell lines. We
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.19.435959; this version posted March 19, 2021. The copyright holder for this preprint(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It ismade available under aCC-BY-NC-ND 4.0 International license.observed stronger binding of the variants D614G and N501Y to the ACE2 surface receptor ofhuman cells, but all tested variants were sensitive to binding inhibition by T. officinale, eitherused before spike protein exposure or thereafter. To date, several studies indicate that theD614G viral lineage is more infectious than the D614 virus (24). Also, the presence ofcharacteristic mutations such as N501Y of, e. g. the so-called UK variant B.1.1.7, result inhigher infectivity than the parent strain which might be due to a higher binding affinity betweenthe spike protein and ACE2 (25). So our findings on T. officinale extracts could here beimportant, as with progression of the pandemic, new virus variants of potential concern willemerge which may also reduce the efficacy of some vaccines or cause increased rates ofreinfections. As mentioned above, an issue in the development of products as prophylaxis forSARS-CoV-2 infection or for slowing the systemic virus spread, is the selectivity towards virusintrusion with low toxicity needed for the host. For current medical indications, no case ofoverdose by T. officinale has been reported (11, 13, 16). The recommended dosage is 4–10 g(about 20-30 mg per ml hot water) up to 3 times per day (Commission E and ESCOP). Basedon the information provided by the European Medicines Agency (EMA) contraindications forthe use of T. officinale are hypersensitivity to the Asteraceae plant family or their activecompounds, liver and biliary diseases, including bile duct obstruction, gallstones andcholangitis, or active peptic ulcer (16). The plant is a significant source of potassium (26, 27)and thus a warning is given because of the possible risk for hyperkalaemia. The use in childrenunder 12 years of age, during pregnancy and lactation has not been established due to lack ofadequate or sufficient data.While ACE2 enzyme activity was not affected by T. officinale extract in the present study, ACE2protein was transiently downregulated in the ACE2 overexpressing lung cell line, whichrequires more attention in ongoing studies. ACE2 is an important zinc-dependent monocarboxypeptidasein the renin-angiotensin pathway, critical in impacting cardiovascular andimmune system. Disruption of the Angiotensin II/Angiotensin-(1-7) balance by ACE2 enzymeactivity inhibition or protein decrease and more circulating Angiotensin II in the system, is e. g.recognised to promote lung injury in the context of COVID-19 disease (28, 29).
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