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

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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [53 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02378768
Contributor : Soline Buisine <>
Submitted on : Monday, November 25, 2019 - 1:07:40 PM
Last modification on : Wednesday, November 27, 2019 - 1:41:08 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Jessica Hernandez, Laurent Hoffer, Bruno Coutard, Gilles Quérat, Philippe Roche, et al.. Optimization of a fragment linking hit toward Dengue and Zika virus NS5 methyltransferases inhibitors. European Journal of Medicinal Chemistry, Elsevier, 2019, 161 (4), pp.323-333. ⟨10.1016/j.ejmech.2018.09.056⟩. ⟨inserm-02378768⟩

Share

Metrics

Record views

26