De Novo Design of α-Helical Lipopeptides Targeting Viral Fusion Proteins: A Promising Strategy for Relatively Broad-Spectrum Antiviral Drug Discovery

J Med Chem. 2018 Oct 11;61(19):8734-8745. doi: 10.1021/acs.jmedchem.8b00890. Epub 2018 Sep 19.

Abstract

Class I enveloped viruses share similarities in their apparent use of a hexameric coiled-coil assembly to drive the merging of virus and host cell membranes. Inhibition of coiled coil-mediated interactions using bioactive peptides that replicate an α-helical chain from the viral fusion machinery has significant antiviral potential. Here, we present the construction of a series of lipopeptides composed of a de novo heptad repeat sequence-based α-helical peptide plus a hydrocarbon tail. Promisingly, the constructs adopted stable α-helical conformations and exhibited relatively broad-spectrum antiviral activities against Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A viruses (IAVs). Together, these findings reveal a new strategy for relatively broad-spectrum antiviral drug discovery by relying on the tunability of the α-helical coiled-coil domains present in all class I fusion proteins and the amphiphilic nature of the individual helices from this multihelix motif.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alphainfluenzavirus / drug effects
  • Amino Acid Sequence
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Coronavirus Infections / drug therapy*
  • Coronavirus Infections / virology
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Influenza, Human / drug therapy*
  • Influenza, Human / virology
  • Lipopeptides / chemistry
  • Lipopeptides / pharmacology*
  • Middle East Respiratory Syndrome Coronavirus / drug effects
  • Protein Conformation, alpha-Helical
  • Viral Fusion Proteins / antagonists & inhibitors*
  • Virus Internalization

Substances

  • Antiviral Agents
  • Lipopeptides
  • Viral Fusion Proteins