This article is part of the network’s archive of useful research information. This article is closed to new comments due to inactivity.  We welcome new content which can be done by submitting an article for review or take part in discussions in an open topic or submit a blog post to take your discussions online.



European Journal of Medicinal Chemistry, 1 January 2019

Jessica Hernandez, Laurent Hoffer, Bruno Coutard, Gilles Querat, Philippe Roche, Xavier Morelli, Etienne Decroly, Karine Barral
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.