Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis

PLoS One. 2018 Mar 22;13(3):e0193982. doi: 10.1371/journal.pone.0193982. eCollection 2018.

Abstract

Although toxoplasmosis is one of the most common parasitic infections worldwide, therapeutic options remain limited. Cathepsins, proteases that play key roles in the pathogenesis of toxoplasmosis and many other protozoan infections, are important potential therapeutic targets. Because both TgCPB and TgCPL play a role in T. gondii invasion, we evaluated the efficacy of the potent, irreversible vinyl sulfone inhibitor, K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl). The inhibitor's toxicity and pharmacokinetic profile have been well-studied because of its in vitro and in vivo activity against a number of parasites. We found that it inhibited both TgCPB (EC50 = 114 nM) and TgCPL (EC50 = 71 nM) in vitro. K11777 also inhibited invasion of human fibroblasts by RH tachyzoites by 71% (p = 0.003) and intracellular replication by >99% (p<0.0001). In vivo, a single dose of K11777 led to 100% survival of chicken embryos in an model of acute toxoplasmosis (p = 0.015 Cox regression analysis). Therefore, K11777 shows promise as a novel therapeutic agent in the treatment of toxoplasmosis, and may prove to be a broadly effective anti-parasitic agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparasitic Agents / pharmacology
  • Cathepsins / metabolism*
  • Chickens
  • Dipeptides / pharmacology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Phenylalanine / analogs & derivatives
  • Piperazines
  • Protozoan Proteins / metabolism*
  • Sulfones / antagonists & inhibitors*
  • Tosyl Compounds
  • Toxoplasmosis / drug therapy*
  • Toxoplasmosis / metabolism
  • Vinyl Compounds / pharmacology*

Substances

  • Antiparasitic Agents
  • Dipeptides
  • Piperazines
  • Protozoan Proteins
  • Sulfones
  • Tosyl Compounds
  • Vinyl Compounds
  • N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl
  • Phenylalanine
  • divinyl sulfone
  • Cathepsins