The Natural Product Cavinafungin Selectively Interferes with Zika and Dengue Virus Replication by Inhibition of the Host Signal Peptidase

Cell Rep. 2017 Apr 18;19(3):451-460. doi: 10.1016/j.celrep.2017.03.071.

Abstract

Flavivirus infections by Zika and dengue virus impose a significant global healthcare threat with no US Food and Drug Administration (FDA)-approved vaccination or specific antiviral treatment available. Here, we present the discovery of an anti-flaviviral natural product named cavinafungin. Cavinafungin is a potent and selectively active compound against Zika and all four dengue virus serotypes. Unbiased, genome-wide genomic profiling in human cells using a novel CRISPR/Cas9 protocol identified the endoplasmic-reticulum-localized signal peptidase as the efficacy target of cavinafungin. Orthogonal profiling in S. cerevisiae followed by the selection of resistant mutants pinpointed the catalytic subunit of the signal peptidase SEC11 as the evolutionary conserved target. Biochemical analysis confirmed a rapid block of signal sequence cleavage of both host and viral proteins by cavinafungin. This study provides an effective compound against the eukaryotic signal peptidase and independent confirmation of the recently identified critical role of the signal peptidase in the replicative cycle of flaviviruses.

Keywords: CRISPR/Cas9; SEC11; SEC11A; Zika virus; cavinafungin; chemogenomic profiling; dengue virus; signal peptidase.

MeSH terms

  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • CRISPR-Cas Systems / genetics
  • Dengue Virus / drug effects
  • Dengue Virus / physiology*
  • Gene Knockdown Techniques
  • Genome, Human
  • Genomics
  • HCT116 Cells
  • Humans
  • Lipopeptides / chemistry
  • Lipopeptides / pharmacology*
  • Membrane Proteins
  • Protein Subunits / metabolism
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Serine Endopeptidases
  • Viral Proteins / metabolism
  • Virus Replication / drug effects*
  • Zika Virus / drug effects
  • Zika Virus / physiology*

Substances

  • Biological Products
  • Lipopeptides
  • Membrane Proteins
  • Protein Subunits
  • Viral Proteins
  • cavinafungin
  • Serine Endopeptidases
  • type I signal peptidase