Optimization of a fragment linking hit toward Dengue and Zika virus NS5 methyltransferases inhibitors.

Antiviral Agents / chemical synthesis Crystallography, X-Ray Dengue Virus / drug effects Dose-Response Relationship, Drug Enzyme Inhibitors / chemical synthesis Methyltransferases / antagonists & inhibitors Microbial Sensitivity Tests Models, Molecular Molecular Structure Structure-Activity Relationship Zika Virus / drug effects
Dengue and Zika viruses Flavivirus NS5 methyltransferase inhibitors Fragment growing Structure-based drug design

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
01 Jan 2019
Historique:
received: 30 05 2018
revised: 15 09 2018
accepted: 23 09 2018
pubmed: 28 10 2018
medline: 19 12 2018
entrez: 28 10 2018
Statut: ppublish

Résumé

No antiviral drugs to treat or prevent life-threatening flavivirus infections such as those caused by mosquito-borne Dengue (DENV) and more recently Zika (ZIKV) viruses are yet available. We aim to develop, through a structure-based drug design approach, novel inhibitors targeting the NS5 AdoMet-dependent mRNA methyltransferase (MTase), a viral protein involved in the RNA capping process essential for flaviviruses replication. Herein, we describe the optimization of a hit (5) identified using fragment-based and structure-guided linking techniques, which binds to a proximal site of the AdoMet binding pocket. X-ray crystallographic structures and computational docking were used to guide our optimization process and lead to compounds 30 and 33 (DENV IC

Identifiants

DOI: 10.1016/j.ejmech.2018.09.056 PMID: 30368131
pubmed: 30368131
pii: S0223-5234(18)30834-1
doi: 10.1016/j.ejmech.2018.09.056
pii:
doi:

Substances chimiques

Antiviral Agents 0
Enzyme Inhibitors 0
Methyltransferases EC 2.1.1.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

323-333

Informations de copyright

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Auteurs

Jessica Hernandez (J)

Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.

Laurent Hoffer (L)

Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.

Bruno Coutard (B)

Aix-Marseille Univ, CNRS, AFMB UMR 7257, Marseille, France.

Gilles Querat (G)

UMR190, Emergence des Pathologies Virales, Aix-Marseille Univ, IRD French Institute of Research for Development, EHESP French School of Public Health, 27 Boulevard Jean Moulin, Marseille, 13005, France.

Philippe Roche (P)

Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.

Xavier Morelli (X)

Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.

Etienne Decroly (E)

Aix-Marseille Univ, CNRS, AFMB UMR 7257, Marseille, France.

Karine Barral (K)

Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: karine.barral@inserm.fr.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Flaviviridae › Flavivirus › Virus de la dengue › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Relation dose-effet des médicaments › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Optimization of a fragment linking hit toward...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Flaviviridae › Flavivirus › Virus Zika › Optimization of a fragment linking hit toward...