Structure-Reactivity Relationships on Substrates and Inhibitors of the Lysine Deacylase Sirtuin 2 from Schistosoma mansoni ( Sm Sirt2)

J Med Chem. 2019 Oct 10;62(19):8733-8759. doi: 10.1021/acs.jmedchem.9b00638. Epub 2019 Sep 20.

Abstract

The only drug currently available for treatment of the neglected disease Schistosomiasis is Praziquantel, and the possible emergence of resistance makes research on novel therapeutic agents necessary and urgent. To this end, the targeting of Schistosoma mansoni epigenetic enzymes, which regulate the parasitic life cycle, emerged as a promising approach. Due to the strong effects of human sirtuin inhibitors on parasite survival and reproduction, Schistosoma sirtuins were postulated as potential therapeutic targets. In vitro testing of synthetic substrates of S. mansoni sirtuin 2 (SmSirt2) and kinetic experiments on a myristoylated peptide demonstrated lysine long-chain deacylation as an intrinsic SmSirt2 activity in addition to its known deacetylase activity for the first time. Focused in vitro screening of the GSK Kinetobox library and structure-activity relationships of identified hits led to the first SmSirt2 inhibitors with activity in the low micromolar range. Several SmSirt2 inhibitors showed potency against both larval schistosomes (viability) and adult worms (pairing, egg laying) in culture without general toxicity to human cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Helminth Proteins / antagonists & inhibitors*
  • Helminth Proteins / metabolism
  • Humans
  • Kinetics
  • Larva / drug effects
  • Larva / metabolism
  • Lysine / chemistry
  • Niacinamide / chemistry
  • Niacinamide / metabolism
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Oxadiazoles / chemistry
  • Oxadiazoles / metabolism
  • Oxadiazoles / pharmacology
  • Oxadiazoles / therapeutic use
  • Peptides / chemistry
  • Peptides / metabolism
  • Peptides / pharmacology
  • Peptides / therapeutic use
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Schistosoma mansoni / growth & development
  • Schistosoma mansoni / metabolism*
  • Schistosomiasis / drug therapy
  • Sirtuin 2 / antagonists & inhibitors*
  • Sirtuin 2 / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Helminth Proteins
  • Oxadiazoles
  • Peptides
  • Pyrimidines
  • Niacinamide
  • Sirtuin 2
  • Lysine