Ulrike Breitinger

German University in Cairo

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Hans‐Georg Breitinger

German University in Cairo

Carmen Villmann

University of Würzburg

Heinrich Sticht

Friedrich-Alexander-Universität Erlangen-Nürnberg

Cord‐Michael Becker

Friedrich-Alexander-Universität Erlangen-Nürnberg

Salma N. Tammam

German University in Cairo

Yasmine M. Mandour

German University in Cairo

Samar Mansour

Ain Shams University

Karim Raafat

Pharos University in Alexandria

Ulrike Holzgrabe

University of Würzburg

Christoph Sotriffer

University of Würzburg

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Parker Hannifin (United States)

129

Miele (Germany)

127

Ulrich Medical (Germany)

108

Elisa (Finland)

108

German University in Cairo

University of Würzburg

Friedrich-Alexander-Universität Erlangen-Nürnberg

Weatherford College

Centre National de la Recherche Scientifique

Inserm

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Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites

Scientific Reports (2023)

Marina Sherif Fam Christine Adel Sedky Nancy O. Turky Hans‐Georg Breitinger Ulrike Breitinger

Abstract 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.

2019-20 coronavirus outbreak

Sars virus

10.1038/s41598-023-31764-9

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Augmentation of glycine receptor alpha3 currents suggests a mechanism for glucose-mediated analgesia

Neuroscience Letters (2015)

Ulrike Breitinger Hans‐Georg Breitinger

10.1016/j.neulet.2015.11.051

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A Novel Glycine Receptor Variant with Startle Disease Affects Syndapin I and Glycinergic Inhibition

Journal of Neuroscience (2020)

Georg Langlhofer Natascha Schaefer Hans Michael Maric Angelo Keramidas Yan Zhang

Glycine receptors (GlyRs) are the major mediators of fast synaptic inhibition in the adult human spinal cord and brainstem. Hereditary mutations to GlyRs can lead to the rare, but potentially fatal, neuromotor disorder hyperekplexia. Most mutations located in the large intracellular domain (TM3-4 loop) of the GlyRα1 impair surface expression levels of the receptors. The novel GLRA1 mutation P366L, located in the TM3-4 loop, showed normal surface expression but reduced chloride currents, and accelerated whole-cell desensitization observed in whole-cell recordings. At the single-channel level, we observed reduced unitary conductance accompanied by spontaneous opening events in the absence of extracellular glycine. Using peptide microarrays and tandem MS-based analysis methods, we show that the proline-rich stretch surrounding P366 mediates binding to syndapin I, an F-BAR domain protein involved in membrane remodeling. The disruption of the noncanonical Src homology 3 recognition motif by P366L reduces syndapin I binding. These data suggest that the GlyRα1 subunit interacts with intracellular binding partners and may therefore play a role in receptor trafficking or synaptic anchoring, a function thus far only ascribed to the GlyRβ subunit. Hence, the P366L GlyRα1 variant exhibits a unique set of properties that cumulatively affect GlyR functionality and thus might explain the neuropathological mechanism underlying hyperekplexia in the mutant carriers. P366L is the first dominant GLRA1 mutation identified within the GlyRα1 TM3-4 loop that affects GlyR physiology without altering protein expression at the whole-cell and surface levels. SIGNIFICANCE STATEMENT We show that the intracellular domain of the inhibitory glycine receptor α1 subunit contributes to trafficking and synaptic anchoring. A proline-rich stretch in this receptor domain forms a noncanonical recognition motif important for the interaction with syndapin I (PACSIN1). The disruption of this motif, as present in a human patient with hyperekplexia led to impaired syndapin I binding. Functional analysis revealed that the altered proline-rich stretch determines several functional physiological parameters of the ion channel (e.g., faster whole-cell desensitization) reduced unitary conductance and spontaneous opening events. Thus, the proline-rich stretch from the glycine receptor α1 subunit represents a multifunctional intracellular protein motif.

Gephyrin

10.1523/jneurosci.2490-19.2020

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Inhibition of SARS CoV Envelope Protein by Flavonoids and Classical Viroporin Inhibitors

Frontiers in Microbiology (2021)

Ulrike Breitinger Nourhan K. M. Ali Heinrich Sticht Hans‐Georg Breitinger

Severe acute respiratory syndrome coronavirus (SARS-CoV), an enveloped single-stranded positive-sense RNA virus, is a member of the genus Betacoronavirus , family Coronaviridae. The SARS-CoV envelope protein E is a small (∼8.4 kDa) channel-forming membrane protein whose sequence is highly conserved between SARS-CoV and SARS-CoV-2. As a viroporin, it is involved in various aspects of the virus life cycle including assembly, budding, envelope formation, virus release, and inflammasome activation. Here, SARS-CoV E protein was recombinantly expressed in HEK293 cells and channel activity and the effects of viroporin inhibitors studied using patch-clamp electrophysiology and a cell viability assay. We introduced a membrane-directing signal peptide to ensure transfer of recombinant E protein to the plasma membrane. E protein expression induced transmembrane currents that were blocked by various inhibitors. In an ion-reduced buffer system, currents were proton-dependent and blocked by viroporin inhibitors rimantadine and amantadine. I-V relationships of recombinant E protein were not pH-dependent in a classical buffer system with high extracellular Na + and high intracellular K + . E-protein mediated currents were inhibited by amantadine and rimantadine, as well as 5-(N,N-hexamethylene)amiloride (HMA). We tested a total of 10 flavonoids, finding inhibitory activity of varying potency. Epigallocatechin and quercetin were most effective, with IC 50 values of 1.5 ± 0.1 and 3.7 ± 0.2 nM, respectively, similar to the potency of rimantadine (IC 50 = 1.7 ± 0.6 nM). Patch-clamp results were independently verified using a modified cell viability assay for viroporin inhibitors. These results contribute to the development of novel antiviral drugs that suppress virus activity and proliferation.

Rimantadine

Coronavirus

10.3389/fmicb.2021.692423

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Citations (36)