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Eur J Med Chem. 2019 Jan 1;161:323-333. doi: 10.1016/j.ejmech.2018.09.056. Epub 2018 Oct 23.

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

Author information

1
Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France.
2
Aix-Marseille Univ, CNRS, AFMB UMR 7257, Marseille, France.
3
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.
4
Aix-Marseille Univ, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address: karine.barral@inserm.fr.

Abstract

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 IC50 = 26 μM and 23 μM; ZIKV IC50 = 28 μM and 19  μM, respectively), two representatives of novel non-nucleoside inhibitors of flavivirus MTases.

KEYWORDS:

Dengue and Zika viruses; Flavivirus NS5 methyltransferase inhibitors; Fragment growing; Structure-based drug design

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