Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites
Marina Sherif Fam, Christine Adel Sedky, Nancy Osama Turky, Hans-Georg Breitinger, Ulrike Breitinger
Scientific Reports, doi:10.1038/s41598-023-31764-9
SARS-CoV-2 has been responsible for the major worldwide pandemic of COVID-19. Despite the enormous success of vaccination campaigns, virus infections are still prevalent and effective antiviral therapies are urgently needed. Viroporins are essential for virus replication and release, and are thus promising therapeutic targets. Here, we studied the expression and function of recombinant ORF3a viroporin of SARS-CoV-2 using a combination of cell viability assays and patch-clamp electrophysiology. ORF3a was expressed in HEK293 cells and transport to the plasma membrane verified by a dot blot assay. Incorporation of a membrane-directing signal peptide increased plasma membrane expression. Cell viability tests were carried out to measure cell damage associated with ORF3a activity, and voltage-clamp recordings verified its channel activity. The classical viroporin inhibitors amantadine and rimantadine inhibited ORF3a channels. A series of ten flavonoids and polyphenolics were studied. Kaempferol, quercetin, epigallocatechin gallate, nobiletin, resveratrol and curcumin were ORF3a inhibitors, with IC 50 values ranging between 1 and 6 µM, while 6-gingerol, apigenin, naringenin and genistein were inactive. For flavonoids, inhibitory activity could be related to the pattern of OH groups on the chromone ring system. Thus, the ORF3a viroporin of SARS-CoV-2 may indeed be a promising target for antiviral drugs. Coronaviruses (CoVs) belong to the order Nidovirales, family Coronaviridae, and subfamily Coronavirinae 1 . They are subdivided into four different genera named α-, β-, γ-, and δ-CoVs 2 . Coronaviruses have been known to infect humans 2-4 , usually causing mild respiratory infections such as a common cold. However, in the past 20 years, two major outbreaks occurred due to crossover of animal β-coronavirus to humans 5 . In 2002-03 humans were infected by bat coronavirus resulting in severe acute respiratory syndrome coronavirus (SARS-CoV) and in 2019, a novel coronavirus of bat origin that had spread to humans, had been discovered in Wuhan, China 6 . This new virus, named SARS-CoV-2, is a member of the β-coronavirus family and is responsible for the ongoing pandemic of COVID-19 1, 7, 8 . SARS-CoVs are enveloped, positive sense single-stranded RNA viruses, with a genome of approximately 30 kb arranged into 14 open reading frames (ORF) encoding 31 proteins [8] [9] [10] [11] . Spike (S), envelope (E), membrane (M) and nucleoprotein (N) are the four structural proteins forming the virus capsid. The S protein binds to the host receptor through the receptor-binding domain in the S1 subunit, while S2 subunit is responsible for membrane fusion 8 . The E protein belongs to the class of viroporins, integral membrane proteins functioning as ion channels and promoting virus release. It was found to be expressed in the ER and the Golgi apparatus forming an ion channel allowing the efflux of cations Na + , K + and Ca 2+ , and is required for pathogenesis and..
Author contributions M.S.F.: design of work, data acquisition and analysis, interpretation of data, revising the manuscript. C.A.S.: data acquisition and analysis, interpretation of data, revising the manuscript. N.O.T.: data acquisition and analysis, interpretation of data, revising the manuscript. H.G.B.: conception, design of work, data acquisition and analysis, interpretation of data, drafting and revising the manuscript. U.B.: conception, design of work, data acquisition and analysis, interpretation of data, drafting, writing and revising the manuscript. All authors have read and approved the submitted manuscript.
Competing interests The authors declare no competing interests.
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