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

Zoë V.F. Wright, Nicholas C. Wu, Rameshwar U. Kadam, Ian A. Wilson, Dennis W. Wolan

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3744-3748
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number16
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Arbidol
  • Bio-layer interferometry
  • Hemagglutinin
  • Influenza
  • Structure-based drug design

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin'. Together they form a unique fingerprint.

  • Cite this