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

Toft-Bertelsen, Trine L.; Jeppesen, Mads Gravers; Tzortzini, Eva; Xue, Kai; Giller, Karin; Becker, Stefan; Mujezinovic, Amer; Bentzen, Bo Hjorth; Andreas, Loren B.; Kolocouris, Antonios; Kledal, Thomas N.

doi:10.1038/s42003-021-02940-2

Cited by 11 publications

(20 citation statements)

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“…While performing these studies, several other groups published electrophysiology data to either support or oppose the SARS-CoV-2 Orf3a viroporin hypothesis. 4,16 Our results from Xenopus oocytes are consistent with Grant and Lester. 16 We propose that the reported SARS-CoV-2 Orf3a current observed by Toft-Bertelsen et al could be contributed by the calcium-activated chloride channel TMEM16A, a known background channel in Xenopus oocytes, also suggested by others.…”

Section: Discussionsupporting

confidence: 90%

“…16 We propose that the reported SARS-CoV-2 Orf3a current observed by Toft-Bertelsen et al could be contributed by the calcium-activated chloride channel TMEM16A, a known background channel in Xenopus oocytes, also suggested by others. 4, 17, 50 Similar to Kern et al , we were able to measure multiple large single channel-like conductances from vesicle-reconstituted SARS-CoV-2 Orf3a in K + , Na + , and Ca 2+ conditions using an atypically high protein to lipid ratio (1:10, wt:wt). 3, 35 These channel-like conductances were not present in samples reconstituted using a standard protein to lipid mixture of 1:100 (wt:wt).…”

Section: Discussionmentioning

confidence: 82%

“…One of these proteins is Open reading frame 3a (Orf3a), a membrane protein that is annotated as a putative viroporin based on previous work and its similarity to SARS-CoV-1, also claimed to be a viroporin. [3][4][5][6] In this paper we determine the structures of SARS-CoV-2 and SARS-CoV-1 Orf3a, measure their functions, and examine the differences between the CoV-2 and CoV-1 proteins.…”

Section: Introductionmentioning

confidence: 99%

“…12, 17, 18 Additionally, SARS-CoV-2 Orf3a viroporin activity has not been studied in mammalian cells, which represents a more native environment for functional studies. 3, 4, 16 We performed a comprehensive structural and functional investigation of SARS-CoV-2 Orf3a. We surveyed the subcellular localization of overexpressed SARS-CoV-2 Orf3a in HEK293 cells and observed co-localization with markers of the plasma membrane and the endocytic pathway, as previously reported.…”

Section: Introductionmentioning

confidence: 99%

“…While pursuing this, several groups reported conflicting findings that support or oppose the SARS-CoV-2 Orf3a viroporin hypothesis. 3, 4, 16 We reasoned that the discrepancy could be due to common experimental problems that arise when characterizing putative ion channels, leading to its misidentification as a viroporin. 12, 17, 18 Additionally, SARS-CoV-2 Orf3a viroporin activity has not been studied in mammalian cells, which represents a more native environment for functional studies.…”

Section: Introductionmentioning

confidence: 99%

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The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

Miller

Houlihan

Matamala

et al. 2022

Preprint

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The severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) and SARS-CoV-1 accessory protein Orf3a colocalizes with markers of the plasma membrane, endocytic pathway, and Golgi apparatus. Some reports have led to annotation of both Orf3a proteins as a viroporin. Here we show that neither SARS-CoV-2 nor SARS-CoV-1 form functional ion conducting pores and that the conductances measured are common contaminants in overexpression and with high levels of protein in reconstitution studies. Cryo-EM structures of both SARS-CoV-2 and SARS-CoV-1 Orf3a display a narrow constriction and the presence of a basic aqueous vestibule, which would not favor cation permeation. We observe enrichment of the late endosomal marker Rab7 upon SARS-CoV-2 Orf3a overexpression, and co-immunoprecipitation with VPS39. Interestingly, SARS-CoV-1 Orf3a does not cause the same cellular phenotype as SARS-CoV-2 Orf3a and does not interact with VPS39. To explain this difference, we find that a divergent, unstructured loop of SARS-CoV-2 Orf3a facilitates its binding with VPS39, a HOPS complex tethering protein involved in late endosome and autophagosome fusion with lysosomes. We suggest that the added loop enhances SARS-CoV-2 Orf3a ability to co-opt host cellular trafficking mechanisms for viral exit or host immune evasion.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

Miller

Houlihan

Matamala

et al. 2022

Preprint

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Ethical challenges of clinical trials with a repurposed drug in outbreaks

Klaś

Strzebońska

Waligóra

2023

Med Health Care and Philos

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Drug repurposing is a strategy of identifying new potential uses for already existing drugs. Many researchers adopted this method to identify treatment or prevention during the COVID-19 pandemic. However, despite the considerable number of repurposed drugs that were evaluated, only some of them were labeled for new indications. In this article, we present the case of amantadine, a drug commonly used in neurology that attracted new attention during the COVID-19 outbreak. This example illustrates some of the ethical challenges associated with the launch of clinical trials to evaluate already approved drugs. In our discussion, we follow the ethics framework for prioritization of COVID-19 clinical trials proposed by Michelle N Meyer and colleagues (2021). We focus on four criteria: social value, scientific validity, feasibility, and consolidation/collaboration. We claim that launching amantadine trials was ethically justified. Although the scientific value was anticipated to be low, unusually, the social value was expected to be high. This was because of significant social interest in the drug. In our view, this strongly supports the need for evidence to justify why the drug should not be prescribed or privately accessed by interested parties. Otherwise, a lack of evidence-based argument could enhance its uncontrolled use. With this paper, we join the discussion on the lessons learned from the pandemic. Our findings will help to improve future efforts to decide on the launch of clinical trials on approved drugs when dealing with the widespread off-label use of the drug.

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Amantadine for COVID-19 treatment (ACT) study: a randomized, double-blinded, placebo-controlled clinical trial

Weis,

Bollerup,

Sund

et al. 2023

Clinical Microbiology and Infection

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

Cited by 11 publications

References 0 publications

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins

Ethical challenges of clinical trials with a repurposed drug in outbreaks

Amantadine for COVID-19 treatment (ACT) study: a randomized, double-blinded, placebo-controlled clinical trial

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