Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Wright, Zoe V. F.¹  Wu, Nicholas C.²  Kadam, Rameshwar U.²  Wilson, Ian A.^2,3  Wolan, Dennis W.¹ 

[1] Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

关键词: Influenza;    Hemagglutinin;    Arbidol;    Structure-based drug design;    Bio-layer interferometry;   

DOI  :  10.1016/j.bmcl.2017.06.074

来源: Elsevier

【 摘 要 】

Influenza is a highly contagious respiratory viral infection responsible for up to 50,000 deaths per annum in the US alone. The need for new therapeutics with novel modes of action is of paramount importance. We determined the X-ray structure of Arbidol with influenza hemagglutinin and found it was located in a distinct binding pocket. Herein, we report a structure-activity relationship study based on the co-complex combined with bio-layer interferometry to assess the binding of our compounds. Addition of a meta-hydroxy group to the thiophenol moiety of Arbidol to replace a structured water molecule in the binding pocket resulted in a dramatic increase in affinity against both H3 (1150-fold) and H1 (98-fold) hemagglutinin subtypes. Our analogues represent novel leads to yield more potent compounds against hemagglutinin that block viral entry. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free