2. Academic Validation
  3. Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein

Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein

  • ACS Nano. 2021 Jul 22;10.1021/acsnano.1c02057. doi: 10.1021/acsnano.1c02057.
Francesca T Bovier 1 2 3,  Ksenia Rybkina 1 2,  Sudipta Biswas 1 4,  Olivia Harder 5,  Tara C Marcink 1 2,  Stefan Niewiesk 5,  Anne Moscona 1 2 6 7,  Christopher A Alabi 4,  Matteo Porotto 1 2 3
Affiliations

Affiliations

  • 1 Center for Host-Pathogen Interaction, Columbia University Vagelos College of Physicians and Surgeons, New York, New York 10032, United States.
  • 2 Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York 10032, United States.
  • 3 Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", 81100 Caserta, Italy.
  • 4 Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.
  • 5 Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, Ohio 43210, United States.
  • 6 Department of Microbiology & Immunology, Columbia University Vagelos College of Physicians and Surgeons, New York, New York 10032, United States.
  • 7 Department of Physiology & Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York 10032, United States.
PMID: 34291895 DOI: 10.1021/acsnano.1c02057
Abstract

Measles virus (MeV) Infection remains a significant public health threat despite ongoing global efforts to increase vaccine coverage. As eradication of MeV stalls, and vulnerable populations expand, effective antivirals against MeV are in high demand. Here, we describe the development of an Antiviral peptide that targets the MeV fusion (F) protein. This Antiviral peptide construct is composed of a carbobenzoxy-d-Phe-l-Phe-Gly (fusion inhibitor peptide; FIP) conjugated to a lipidated MeV F C-terminal heptad repeat (HRC) domain derivative. Initial in vitro testing showed high Antiviral potency and specific targeting of MeV F-associated cell plasma membranes, with minimal cytotoxicity. The FIP and HRC-derived peptide conjugates showed synergistic Antiviral activities when administered individually. However, their chemical conjugation resulted in markedly increased Antiviral potency. In vitro mechanistic experiments revealed that the FIP-HRC lipid conjugate exerted its Antiviral activity predominantly through stabilization of the prefusion F, while HRC-derived Peptides alone act predominantly on the F protein after its activation. Coupled with in vivo experiments showing effective prevention of MeV Infection in cotton rats, FIP-HRC lipid conjugates show promise as potential MeV antivirals via specific targeting and stabilization of the prefusion MeV F structure.

Keywords

antiviral therapy; fusion inhibitor; fusion protein; lipopeptide; measles.

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