Characterization of SPP inhibitors suppressing propagation of HCV and protozoa

Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):E10782-E10791. doi: 10.1073/pnas.1712484114. Epub 2017 Nov 29.

Abstract

Signal peptide peptidase (SPP) is an intramembrane aspartic protease involved in the maturation of the core protein of hepatitis C virus (HCV). The processing of HCV core protein by SPP has been reported to be critical for the propagation and pathogenesis of HCV. Here we examined the inhibitory activity of inhibitors for γ-secretase, another intramembrane cleaving protease, against SPP, and our findings revealed that the dibenzoazepine-type structure in the γ-secretase inhibitors is critical for the inhibition of SPP. The spatial distribution showed that the γ-secretase inhibitor compound YO-01027 with the dibenzoazepine structure exhibits potent inhibiting activity against SPP in vitro and in vivo through the interaction of Val223 in SPP. Treatment with this SPP inhibitor suppressed the maturation of core proteins of all HCV genotypes without the emergence of drug-resistant viruses, in contrast to the treatment with direct-acting antivirals. YO-01027 also efficiently inhibited the propagation of protozoa such as Plasmodium falciparum and Toxoplasma gondii These data suggest that SPP is an ideal target for the development of therapeutics not only against chronic hepatitis C but also against protozoiasis.

Keywords: HCV; Protozoa; SPP; pathogenesis; propagation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Animals
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cell Line
  • Dibenzazepines / chemistry
  • Dibenzazepines / pharmacology*
  • HEK293 Cells
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Plasmodium falciparum / drug effects
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Toxoplasma / drug effects
  • Viral Core Proteins / antagonists & inhibitors
  • Virus Replication / drug effects

Substances

  • Antiprotozoal Agents
  • Antiviral Agents
  • Dibenzazepines
  • Protease Inhibitors
  • Viral Core Proteins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • signal peptide peptidase