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

Fingerprint

Leishmania mexicana
Cysteine Proteases
Parasites
Oxadiazoles
Isoxazoles
Cysteine Proteinase Inhibitors
Antiparasitic Agents
Parasitic Diseases
Leishmaniasis
Papain
Chagas Disease
Eukaryota
Screening

Keywords

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

Cite this

Steert, Koen ; Berg, Maya ; Mottram, Jeremy C. ; Westrop, Gareth D. ; Coombs, Graham H. ; Cos, Paul ; Maes, Louis ; Joossens, Jurgen ; Van der Veken, Pieter ; Haemers, Achiel ; Augustyns, Koen. / alpha-Ketoheterocycles as inhibitors of leishmania mexicana cysteine protease CPB. In: ChemMedChem. 2010 ; Vol. 5, No. 10. pp. 1734-1748.
@article{2926c951923b416fb42cf4ad0345f65b,
title = "alpha-Ketoheterocycles as inhibitors of leishmania mexicana cysteine protease CPB",
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.",
keywords = "cysteine proteases, inhibitors, ketoheterocycles, parasite CPB, trypanosomas, blood-stream forms, trypanosoma-brucei, TH1 response, cathepsin-K, in-vitro, proteinase, virulence, expression, design, differentation",
author = "Koen Steert and Maya Berg and Mottram, {Jeremy C.} and Westrop, {Gareth D.} and Coombs, {Graham H.} and Paul Cos and Louis Maes and Jurgen Joossens and {Van der Veken}, Pieter and Achiel Haemers and Koen Augustyns",
year = "2010",
month = "10",
day = "4",
doi = "10.1002/cmdc.201000265",
language = "English",
volume = "5",
pages = "1734--1748",
journal = "ChemMedChem",
issn = "1860-7179",
number = "10",

}

Steert, K, Berg, M, Mottram, JC, Westrop, GD, Coombs, GH, Cos, P, Maes, L, Joossens, J, Van der Veken, P, Haemers, A & Augustyns, K 2010, 'alpha-Ketoheterocycles as inhibitors of leishmania mexicana cysteine protease CPB', ChemMedChem, vol. 5, no. 10, pp. 1734-1748. https://doi.org/10.1002/cmdc.201000265

alpha-Ketoheterocycles as inhibitors of leishmania mexicana cysteine protease CPB. / Steert, Koen; Berg, Maya; Mottram, Jeremy C.; Westrop, Gareth D.; Coombs, Graham H.; Cos, Paul; Maes, Louis; Joossens, Jurgen; Van der Veken, Pieter; Haemers, Achiel; Augustyns, Koen.

In: ChemMedChem, Vol. 5, No. 10, 04.10.2010, p. 1734-1748.

Research output: Contribution to journalArticle

TY - JOUR

T1 - alpha-Ketoheterocycles as inhibitors of leishmania mexicana cysteine protease CPB

AU - Steert, Koen

AU - Berg, Maya

AU - Mottram, Jeremy C.

AU - Westrop, Gareth D.

AU - Coombs, Graham H.

AU - Cos, Paul

AU - Maes, Louis

AU - Joossens, Jurgen

AU - Van der Veken, Pieter

AU - Haemers, Achiel

AU - Augustyns, Koen

PY - 2010/10/4

Y1 - 2010/10/4

N2 - 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.

AB - 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.

KW - cysteine proteases

KW - inhibitors

KW - ketoheterocycles

KW - parasite CPB

KW - trypanosomas

KW - blood-stream forms

KW - trypanosoma-brucei

KW - TH1 response

KW - cathepsin-K

KW - in-vitro

KW - proteinase

KW - virulence

KW - expression

KW - design

KW - differentation

UR - http://www.scopus.com/inward/record.url?scp=77957688564&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201000265

DO - 10.1002/cmdc.201000265

M3 - Article

VL - 5

SP - 1734

EP - 1748

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

IS - 10

ER -