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  • Title: Optimization of a fragment linking hit toward Dengue and Zika virus NS5 methyltransferases inhibitors.
    Author: Hernandez J, Hoffer L, Coutard B, Querat G, Roche P, Morelli X, Decroly E, Barral K.
    Journal: Eur J Med Chem; 2019 Jan 01; 161():323-333. PubMed ID: 30368131.
    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.
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