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Neuropeptides, New Ligands of SARS-CoV-2 Nucleoprotein, a Potential Link between Replication, Inflammation and Neurotransmission.
Henri, Julien; Minder, Laetitia; Mohanasundaram, Kevin; Dilly, Sébastien; Goupil-Lamy, Anne; Di Primo, Carmelo; Slama Schwok, Anny.
  • Henri J; Laboratoire de Biologie Computationnelle et Quantitative, Institut de Biologie Paris-Seine, UMR-CNRS 7238, Sorbonne Université, F-75005 Paris, France.
  • Minder L; Institut Européen de Chimie et Biologie (IECB), CNRS, INSERM UAR 3033, US001, Univ. Bordeaux, F-33000 Bordeaux, France.
  • Mohanasundaram K; Saint Antoine Hospital, Centre de Recherche Saint Antoine, Sorbonne Université, Biology and Cancer Therapeutics, INSERM U938, F-75231 Paris, France.
  • Dilly S; Saint Antoine Hospital, Centre de Recherche Saint Antoine, Sorbonne Université, Biology and Cancer Therapeutics, INSERM U938, F-75231 Paris, France.
  • Goupil-Lamy A; Biovia, Dassault Systèmes, 10 Rue Marcel Dassault, CS40501, CEDEX, F-78946 Vélizy-Villacoublay, France.
  • Di Primo C; CNRS, INSERM, ARNA, UMR 5320, U1212, IECB, Univ. Bordeaux, F-33000 Bordeaux, France.
  • Slama Schwok A; Saint Antoine Hospital, Centre de Recherche Saint Antoine, Sorbonne Université, Biology and Cancer Therapeutics, INSERM U938, F-75231 Paris, France.
Molecules ; 27(22)2022 Nov 21.
Article in English | MEDLINE | ID: covidwho-2123759
ABSTRACT
This work identifies new ligands of the nucleoprotein N of SARS-CoV-2 by in silico screening, which used a new model of N, built from an Alphafold model refined by molecular dynamic simulations. The ligands were neuropeptides, such as substance P (1-7) and enkephalin, bound at a large site of the C-terminal or associated with the N-terminal ß-sheet. The BA4 and BA5 Omicron variants of N also exhibited a large site as in wt N, and an increased flexibility of the BA5 variant, enabling substance P binding. The binding sites of some ligands deduced from modeling in wt N were assessed by mutation studies in surface plasmon resonance experiments. Dynamic light scattering showed that the ligands impeded RNA binding to N, which likely inhibited replication. We suggest that the physiological role of these neuropeptides in neurotransmission, pain and vasodilation for cholecystokinin and substance P could be altered by binding to N. We speculate that N may link between viral replication and multiple pathways leading to long COVID-19 symptoms. Therefore, N may constitute a "danger hub" that needs to be inhibited, even at high cost for the host. Antivirals targeted to N may therefore reduce the risk of brain fog and stroke, and improve patients' health.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Neuropeptides / COVID-19 Type of study: Prognostic study Topics: Long Covid / Variants Limits: Humans Language: English Journal subject: Biology Year: 2022 Document Type: Article Affiliation country: Molecules27228094

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Neuropeptides / COVID-19 Type of study: Prognostic study Topics: Long Covid / Variants Limits: Humans Language: English Journal subject: Biology Year: 2022 Document Type: Article Affiliation country: Molecules27228094