دورية أكاديمية
Zika virus replication is impaired by a selective agonist of the TRPML2 ion channel.
| العنوان: | Zika virus replication is impaired by a selective agonist of the TRPML2 ion channel. |
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| المؤلفون: | Schwickert KK; Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University, Jena, Germany; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany; Department of Chemistry, Johannes Gutenberg-University, 55122, Mainz, Germany., Glitscher M; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany., Bender D; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany., Benz NI; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany., Murra R; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany., Schwickert K; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University, 55122, Mainz, Germany., Pfalzgraf S; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany., Schirmeister T; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg-University, 55122, Mainz, Germany., Hellmich UA; Faculty of Chemistry and Earth Sciences, Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University, Jena, Germany; Centre for Biomolecular Magnetic Resonance (BMRZ), Goethe University, Frankfurt, Germany; Cluster of Excellence 'Balance of the Microverse', Friedrich Schiller University, Jena, Germany. Electronic address: ute.hellmich@uni-jena.de., Hildt E; Department of Virology, Paul-Ehrlich-Institut, 63225, Langen, Germany. Electronic address: eberhard.hildt@pei.de. |
| المصدر: | Antiviral research [Antiviral Res] 2024 Aug; Vol. 228, pp. 105940. Date of Electronic Publication: 2024 Jun 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8109699 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9096 (Electronic) Linking ISSN: 01663542 NLM ISO Abbreviation: Antiviral Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Amsterdam : Elsevier Original Publication: [Amsterdam ; New York : Elsevier/North-Holland Biomedical Press, c1981- |
| مواضيع طبية MeSH: | Zika Virus*/drug effects , Zika Virus*/physiology , Virus Replication*/drug effects , Antiviral Agents*/pharmacology , Transient Receptor Potential Channels*/agonists , Transient Receptor Potential Channels*/metabolism , Zika Virus Infection*/virology , Zika Virus Infection*/drug therapy, Humans ; Chlorocebus aethiops ; Animals ; Vero Cells ; Cholesterol/metabolism ; Lysosomes/drug effects ; Lysosomes/metabolism ; Cell Line ; HEK293 Cells ; Phthalimides ; Quinolines |
| مستخلص: | The flavivirus genus includes human pathogenic viruses such as Dengue (DENV), West Nile (WNV) and Zika virus (ZIKV) posing a global health threat due to limited treatment options. Host ion channels are crucial for various viral life cycle stages, but their potential as targets for antivirals is often not fully realized due to the lack of selective modulators. Here, we observe that treatment with ML2-SA1, an agonist for the human endolysosomal cation channel TRPML2, impairs ZIKV replication. Upon ML2-SA1 treatment, levels of intracellular genomes and number of released virus particles of two different ZIKV isolates were significantly reduced and cells displayed enlarged vesicular structures and multivesicular bodies with ZIKV envelope protein accumulation. However, no increased ZIKV degradation in lysosomal compartments was observed. Rather, the antiviral effect of ML2-SA1 seemed to manifest by the compound's negative impact on genome replication. Moreover, ML2-SA1 treatment also led to intracellular cholesterol accumulation. ZIKV and many other viruses including the Orthohepevirus Hepatitis E virus (HEV) rely on the endolysosomal system and are affected by intracellular cholesterol levels to complete their life cycle. Since we observed that ML2-SA1 also negatively impacted HEV infections in vitro, this compound may harbor a broader antiviral potential through perturbing the intracellular cholesterol distribution. Besides indicating that TRPML2 may be a promising target for combatting viral infections, we uncover a tentative connection between this protein and cholesterol distribution within the context of infectious diseases. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Cholesterol; Flavivirus; Hepatitis E virus; TRP channel; TRPML; Zika virus |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Transient Receptor Potential Channels) 0 (Mcoln2 protein, human) 0 (ML-SA1 compound) 97C5T2UQ7J (Cholesterol) 0 (Phthalimides) 0 (Quinolines) |
| تواريخ الأحداث: | Date Created: 20240620 Date Completed: 20240715 Latest Revision: 20240813 |
| رمز التحديث: | 20240813 |
| DOI: | 10.1016/j.antiviral.2024.105940 |
| PMID: | 38901736 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1872-9096 |
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| DOI: | 10.1016/j.antiviral.2024.105940 |