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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.
  • Svetlova J; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
  • Knizhnik E; Department of Molecular and Translational Medicine, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia.
  • Manuvera V; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
  • Severov V; Department of Molecular and Translational Medicine, Moscow Institute of Physics and Technology, 141701 Dolgoprudny, Russia.
  • Shirokov D; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
  • Grafskaia E; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
  • Bobrovsky P; K.I. Skryabin Moscow State Academy of Veterinary Medicine and Biotechnology, 109472 Moscow, Russia.
  • Matyugina E; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
  • Khandazhinskaya A; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
  • Kozlovskaya L; Engelhardt Institute of Molecular Biology, Russian Academy of Science, 119991 Moscow, Russia.
  • Miropolskaya N; Engelhardt Institute of Molecular Biology, Russian Academy of Science, 119991 Moscow, Russia.
  • Aralov A; Chumakov Federal Scientific Center for Research, Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819 Moscow, Russia.
  • Khodarovich Y; Institute of Molecular Genetics, National Research Centre 'Kurchatov Institute', 123182 Moscow, Russia.
  • Tsvetkov V; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, 117997 Moscow, Russia.
  • Kochetkov S; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, RAS, 117997 Moscow, Russia.
  • Lazarev V; Research and Educational Resource Center for Cellular Technologies, The Peoples' Friendship University of Russia, 117198 Moscow, Russia.
  • Varizhuk A; Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia.
Int J Mol Sci ; 23(23)2022 Dec 03.
Article in English | MEDLINE | ID: covidwho-2143246
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Perylene / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232315281

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Perylene / COVID-19 Type of study: Prognostic study Limits: Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms232315281