SARS-CoV-2 ORF7b: is a bat virus protein homologue a major cause of COVID-19 symptoms?

Fogeron, Marie‐Laure; Montserret, Roland; Zehnder, Johannes; Nguyen, Minh-Ha; Dujardin, Marie; Brigandat, Louis; Cole, Laura K.; Ninot-Pedrosa, Martí; Lecoq, Lauriane; Meier, Beat H.; Böckmann, Anja

doi:10.1101/2021.02.05.428650

Cited by 20 publications

(22 citation statements)

References 60 publications

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“…Although ORF7b functioned as an ion channel and showed some homology to Protein E, we observed no effect of amantadine on ORF7b. The suggested pentameric model for ORF7b 40 is based on similarity to leucine zipper proteins and not homology to Protein E. Based on our sequence alignment, N15 in Protein E, which we here suggested interacting with the ammonium group of amantadine or the guanidinium of HMA with the drugs in the outward orientation, is equivalent to D8 in ORF7b. This aspartic acid residue can form ionic hydrogen bonding interactions with the ammonium group of amantadine or guanidinium group of HMA.…”

Section: Discussionmentioning

confidence: 87%

“…In SARS-CoV-1, ORF7b has been identified as a transmembrane protein with an external N-terminus and cytoplasmic C-terminus 39 . Moreover, ORF7b from SARS-CoV-2 was recently suggested to assemble into a pentamer and to be involved in heart arrhythmia and loss of smell through interactions with other proteins 40 . We discovered amino-acid sequence homology of the core of ORF7b to Protein E from SARS-CoV-1 and -2 in a consensus region containing three conserved Phe residues (Supplementary Fig.…”

Section: Sars-cov-2 Orf7b and Orf10 Function As Ion Channelsmentioning

confidence: 99%

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Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro

et al. 2021

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The dire need for COVID-19 treatments has inspired strategies of repurposing approved drugs. Amantadine has been suggested as a candidate, and cellular as well as clinical studies have indicated beneficial effects of this drug. We demonstrate that amantadine and hexamethylene-amiloride (HMA), but not rimantadine, block the ion channel activity of Protein E from SARS-CoV-2, a conserved viroporin among coronaviruses. These findings agree with their binding to Protein E as evaluated by solution NMR and molecular dynamics simulations. Moreover, we identify two novel viroporins of SARS-CoV-2; ORF7b and ORF10, by showing ion channel activity in a X. laevis oocyte expression system. Notably, amantadine also blocks the ion channel activity of ORF10, thereby providing two ion channel targets in SARS-CoV-2 for amantadine treatment in COVID-19 patients. A screen of known viroporin inhibitors on Protein E, ORF7b, ORF10 and Protein 3a from SARS-CoV-2 revealed inhibition of Protein E and ORF7b by emodin and xanthene, the latter also blocking Protein 3a. This illustrates a general potential of well-known ion channel blockers against SARS-CoV-2 and specifically a dual molecular basis for the promising effects of amantadine in COVID-19 treatment. We therefore propose amantadine as a novel, cheap, readily available and effective way to treat COVID-19.

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Section: Discussionmentioning

confidence: 87%

Section: Sars-cov-2 Orf7b and Orf10 Function As Ion Channelsmentioning

confidence: 99%

Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro

et al. 2021

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“…Because ORF7b functional analysis remains to be performed, some authors have shown that this protein assembles into stable multimers through a leucine zipper. They have hypothesized that ORF7b could potentially interfere with some cellular processes that underlie some common symptoms of SARS-CoV-2 infection involving leucine zipper formation and epithelial cell-cell adhesion, such as heart rate dysregulation ( 47 ).…”

Section: Accessory Proteins Of Sars-cov-2mentioning

confidence: 99%

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

et al. 2021

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There are still many unanswered questions concerning viral SARS-CoV-2 pathogenesis in COVID-19. Accessory proteins in SARS-CoV-2 consist of eleven viral proteins whose roles during infection are still not completely understood. Here, a review on the current knowledge of SARS-CoV-2 accessory proteins is summarized updating new research that could be critical in understanding SARS-CoV-2 interaction with the host. Some accessory proteins such as ORF3b, ORF6, ORF7a and ORF8 have been shown to be important IFN-I antagonists inducing an impairment in the host immune response. In addition, ORF3a is involved in apoptosis whereas others like ORF9b and ORF9c interact with cellular organelles leading to suppression of the antiviral response in infected cells. However, possible roles of ORF7b and ORF10 are still awaiting to be described. Also, ORF3d has been reassigned. Relevant information on the knowns and the unknowns in these proteins is analyzed, which could be crucial for further understanding of SARS-CoV-2 pathogenesis and to design strategies counteracting their actions evading immune responses in COVID-19.

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“…It has been characterized as an important multimeric structural component of the virions and seems to be necessary for the infection. [ 48 , 49 ] Thus, it is possible that mutations or conditions that alter the function of ORF3a or ORF7b may affect the spreading of infection by SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

In silico analysis of the aggregation propensity of the SARS-CoV-2 proteome: Insight into possible cellular pathologies

Flores-León

Lázaro

Shvachiy

et al. 2021

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The coronavirus disease 19 emerged in 2020 is caused by the SARS-CoV-2 virus. The pandemic triggered a turmoil in public health and is having a tremendous social and economic impact around the globe. Upon entry into host cells, the SARS-CoV-2 virus hijacks cellular machineries to produce and maintain its own proteins, spreading the infection. Although the disease is known for prominent respiratory symptoms, accumulating evidence is also demonstrating the involvement of the central nervous system, with possible mid- and long-term neurological consequences. In this study, we conducted a detailed bioinformatic analysis of the SARS-CoV-2 proteome aggregation propensity by using several complementary computational tools. Our study identified 10 aggregation prone proteins in the reference SARS-CoV-2 strain: the non-structural proteins Nsp4, Nsp6 and Nsp7 as well as ORF3a, ORF6, ORF7a, ORF7b, ORF10, CovE and CovM. By searching for the available mutants of each protein, we have found that most proteins are conserved, while ORF3a and ORF7b are variable and characterized by the occurrence of a large number of mutants with increased aggregation propensity. The geographical distribution of the mutants revealed interesting differences in the localization of aggregation-prone mutants of each protein. Aggregation-prone mutants of ORF7b were found in 7 European countries, whereas those of ORF3a in only 2. Aggregation-prone sequences of ORF7b, but not of ORF3a, were identified in Australia, India, Nepal, China, and Thailand. Our results are important for future analysis of a possible correlation between higher transmissibility and infection, as well as the presence of neurological symptoms with aggregation propensity of SARS-CoV-2 proteins.

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SARS-CoV-2 ORF7b: is a bat virus protein homologue a major cause of COVID-19 symptoms?

Cited by 20 publications

References 60 publications

Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro

Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro

SARS-CoV-2 Accessory Proteins in Viral Pathogenesis: Knowns and Unknowns

In silico analysis of the aggregation propensity of the SARS-CoV-2 proteome: Insight into possible cellular pathologies

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