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Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro
The life cycle of severe acute respiratory syndrome coronavirus 2 includes several steps that are supposedly mediated by liquid–liquid phase separation (LLPS) of the viral nucleocapsid protein (N) and genomic RNA. To facilitate the rational design of LLPS-targeting therapeutics, we modeled N-RNA bio...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738865/ https://www.ncbi.nlm.nih.gov/pubmed/36499608 http://dx.doi.org/10.3390/ijms232315281 |
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author | Svetlova, Julia Knizhnik, Ekaterina Manuvera, Valentin Severov, Vyacheslav Shirokov, Dmitriy Grafskaia, Ekaterina Bobrovsky, Pavel Matyugina, Elena Khandazhinskaya, Anastasia Kozlovskaya, Liubov Miropolskaya, Nataliya Aralov, Andrey Khodarovich, Yuri Tsvetkov, Vladimir Kochetkov, Sergey Lazarev, Vassili Varizhuk, Anna |
author_facet | Svetlova, Julia Knizhnik, Ekaterina Manuvera, Valentin Severov, Vyacheslav Shirokov, Dmitriy Grafskaia, Ekaterina Bobrovsky, Pavel Matyugina, Elena Khandazhinskaya, Anastasia Kozlovskaya, Liubov Miropolskaya, Nataliya Aralov, Andrey Khodarovich, Yuri Tsvetkov, Vladimir Kochetkov, Sergey Lazarev, Vassili Varizhuk, Anna |
author_sort | Svetlova, Julia |
collection | PubMed |
description | The life cycle of severe acute respiratory syndrome coronavirus 2 includes several steps that are supposedly mediated by liquid–liquid phase separation (LLPS) of the viral nucleocapsid protein (N) and genomic RNA. To facilitate the rational design of LLPS-targeting therapeutics, we modeled N-RNA biomolecular condensates in vitro and analyzed their sensitivity to several small-molecule antivirals. The model condensates were obtained and visualized under physiological conditions using an optimized RNA sequence enriched with N-binding motifs. The antivirals were selected based on their presumed ability to compete with RNA for specific N sites or interfere with non-specific pi–pi/cation–pi interactions. The set of antivirals included fleximers, 5′-norcarbocyclic nucleoside analogs, and perylene-harboring nucleoside analogs as well as non-nucleoside amphiphilic and hydrophobic perylene derivatives. Most of these antivirals enhanced the formation of N-RNA condensates. Hydrophobic perylene derivatives and 5′-norcarbocyclic derivatives caused up to 50-fold and 15-fold enhancement, respectively. Molecular modeling data argue that hydrophobic compounds do not hamper specific N-RNA interactions and may promote non-specific ones. These findings shed light on the determinants of potent small-molecule modulators of viral LLPS. |
format | Online Article Text |
id | pubmed-9738865 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97388652022-12-11 Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro Svetlova, Julia Knizhnik, Ekaterina Manuvera, Valentin Severov, Vyacheslav Shirokov, Dmitriy Grafskaia, Ekaterina Bobrovsky, Pavel Matyugina, Elena Khandazhinskaya, Anastasia Kozlovskaya, Liubov Miropolskaya, Nataliya Aralov, Andrey Khodarovich, Yuri Tsvetkov, Vladimir Kochetkov, Sergey Lazarev, Vassili Varizhuk, Anna Int J Mol Sci Article The life cycle of severe acute respiratory syndrome coronavirus 2 includes several steps that are supposedly mediated by liquid–liquid phase separation (LLPS) of the viral nucleocapsid protein (N) and genomic RNA. To facilitate the rational design of LLPS-targeting therapeutics, we modeled N-RNA biomolecular condensates in vitro and analyzed their sensitivity to several small-molecule antivirals. The model condensates were obtained and visualized under physiological conditions using an optimized RNA sequence enriched with N-binding motifs. The antivirals were selected based on their presumed ability to compete with RNA for specific N sites or interfere with non-specific pi–pi/cation–pi interactions. The set of antivirals included fleximers, 5′-norcarbocyclic nucleoside analogs, and perylene-harboring nucleoside analogs as well as non-nucleoside amphiphilic and hydrophobic perylene derivatives. Most of these antivirals enhanced the formation of N-RNA condensates. Hydrophobic perylene derivatives and 5′-norcarbocyclic derivatives caused up to 50-fold and 15-fold enhancement, respectively. Molecular modeling data argue that hydrophobic compounds do not hamper specific N-RNA interactions and may promote non-specific ones. These findings shed light on the determinants of potent small-molecule modulators of viral LLPS. MDPI 2022-12-03 /pmc/articles/PMC9738865/ /pubmed/36499608 http://dx.doi.org/10.3390/ijms232315281 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Svetlova, Julia Knizhnik, Ekaterina Manuvera, Valentin Severov, Vyacheslav Shirokov, Dmitriy Grafskaia, Ekaterina Bobrovsky, Pavel Matyugina, Elena Khandazhinskaya, Anastasia Kozlovskaya, Liubov Miropolskaya, Nataliya Aralov, Andrey Khodarovich, Yuri Tsvetkov, Vladimir Kochetkov, Sergey Lazarev, Vassili Varizhuk, Anna Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro |
title | Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro |
title_full | Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro |
title_fullStr | Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro |
title_full_unstemmed | Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro |
title_short | Nucleoside Analogs and Perylene Derivatives Modulate Phase Separation of SARS-CoV-2 N Protein and Genomic RNA In Vitro |
title_sort | nucleoside analogs and perylene derivatives modulate phase separation of sars-cov-2 n protein and genomic rna in vitro |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9738865/ https://www.ncbi.nlm.nih.gov/pubmed/36499608 http://dx.doi.org/10.3390/ijms232315281 |
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