2. Academic Validation
  3. Inhibition of H1 and H5 Influenza A Virus Entry by Diverse Macrocyclic Peptides Targeting the Hemagglutinin Stem Region

Inhibition of H1 and H5 Influenza A Virus Entry by Diverse Macrocyclic Peptides Targeting the Hemagglutinin Stem Region

  • ACS Chem Biol. 2022 Sep 16;17(9):2425-2436. doi: 10.1021/acschembio.2c00040.
Mirte N Pascha 1,  Vito Thijssen 2,  Julia E Egido 1 2,  Mirte W Linthorst 3,  Jipke H van Lanen 1,  David A A van Dongen 2,  Antonius J P Hopstaken 4,  Frank J M van Kuppeveld 1,  Joost Snijder 3,  Cornelis A M de Haan 1,  Seino A K Jongkees 2 4
Affiliations

Affiliations

  • 1 Section Virology, Division Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands.
  • 2 Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
  • 3 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
  • 4 Department of Chemistry and Pharmaceutical Sciences, Amsterdam Institute for Molecular and Life Sciences, VU Amsterdam, de Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
PMID: 35926224 DOI: 10.1021/acschembio.2c00040
Abstract

Influenza A viruses pose a serious pandemic risk, while generation of efficient vaccines against seasonal variants remains challenging. There is thus a pressing need for new treatment options. We report here a set of macrocyclic Peptides that inhibit influenza A virus Infection at low nanomolar concentrations by binding to hemagglutinin, selected using ultrahigh-throughput screening of a diverse peptide library. The Peptides are active against both H1 and H5 variants, with no detectable cytotoxicity. Despite the high sequence diversity across hits, all tested Peptides were found to bind to the same region in the hemagglutinin stem by HDX-MS epitope mapping. A mutation in this region identified in an escape variant confirmed the binding site. This stands in contrast to the immunodominance of the head region for antibody binding and suggests that macrocyclic Peptides from in vitro display may be well suited for finding new druggable sites not revealed by Antibodies. Functional analysis indicates that these Peptides stabilize the prefusion conformation of the protein and thereby prevent virus-cell fusion. High-throughput screening of macrocyclic Peptides is thus shown here to be a powerful method for the discovery of novel broadly acting viral fusion inhibitors with therapeutic potential.

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