Aniline-Based Inhibitors of Influenza H1N1 Virus Acting on Hemagglutinin-Mediated Fusion

  • J Med Chem. 2018 Jan 11;61(1):98-118. doi: 10.1021/acs.jmedchem.7b00908.
Rosana Leiva  1 ,  Marta Barniol-Xicota  1 ,  Sandra Codony  1 ,  Tiziana Ginex  2 ,  Evelien Vanderlinden  3 ,  Marta Montes  1 ,  Michael Caffrey  4 ,  F Javier Luque  2 ,  Lieve Naesens  3 ,  Santiago Vázquez  1
Affiliations
  • 1. Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona , Av. Joan XXIII, 27-31, Barcelona E-08028, Spain.
  • 2. Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), Universitat de Barcelona , Av. Prat de la Riba 171, Santa Coloma de Gramanet E-08921, Spain.
  • 3. Rega Institute for Medical Research, KU Leuven , B-3000 Leuven, Belgium.
  • 4. Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago , 900 South Ashland Avenue, Chicago, Illinois 60607, United States.
PMID: 29220568 DOI: 10.1021/acs.jmedchem.7b00908
Abstract

Two series of easily accessible anilines were identified as inhibitors of influenza A virus subtype H1N1, and extensive chemical synthesis and analysis of the structure-activity relationship were performed. The compounds were shown to interfere with low pH-induced membrane fusion mediated by the H1 and H5 (group 1) hemagglutinin (HA) subtypes. A combination of virus resistance, HA interaction, and molecular dynamics simulation studies elucidated the binding site of these aniline-based influenza fusion inhibitors, which significantly overlaps with the pocket occupied by some H3 HA-specific inhibitors, indicating the high relevance of this cavity for drug design.