alpha-Ketoheterocycles as inhibitors of leishmania mexicana cysteine protease CPB

Koen Steert, Maya Berg, Jeremy C. Mottram, Gareth D. Westrop, Graham H. Coombs, Paul Cos, Louis Maes, Jurgen Joossens, Pieter Van der Veken, Achiel Haemers, Koen Augustyns

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes and also play pivotal roles in the biology of parasites. Inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas disease, and leishmaniasis. Inspired by the in vivo antiparasitic activity of the vinylsulfone-based cysteine protease inhibitors, a series of alpha-ketoheterocycles were developed as reversible inhibitors of a recombinant L. mexicana cysteine protease, CPB2.8. Three isoxazoles and especially one oxadiazole compound are potent reversible inhibitors of CPB2.8; however, in vitro whole-organism screening against a panel of protozoan parasites did not fully correlate with the observed inhibition of the cysteine protease.

Original languageEnglish
Pages (from-to)1734-1748
Number of pages15
JournalChemMedChem
Volume5
Issue number10
DOIs
Publication statusPublished - 4 Oct 2010

Keywords

  • cysteine proteases
  • inhibitors
  • ketoheterocycles
  • parasite CPB
  • trypanosomas
  • blood-stream forms
  • trypanosoma-brucei
  • TH1 response
  • cathepsin-K
  • in-vitro
  • proteinase
  • virulence
  • expression
  • design
  • differentation

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