Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB

Jörg Schröder, Sandra Noack, Richard J Marhöfer, Jeremy C Mottram, Graham H Coombs, Paul M Selzer

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)
79 Downloads (Pure)

Abstract

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases.
Original languageEnglish
Article numbere77460
Number of pages12
JournalPLOS One
Volume8
Issue number10
DOIs
Publication statusPublished - 16 Oct 2013

Keywords

  • cysteine protease
  • eukaryotes
  • parasitic diseases
  • Leishmania mexicana

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