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The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo

BACKGROUND: Current chemotherapy of human African trypanosomiasis or sleeping sickness relies on drugs developed decades ago, some of which show toxic side effects. One promising line of research towards the development of novel anti-trypanosomal drugs are small-molecule inhibitors of Trypanosoma br...

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Autores principales: Scory, Stefan, Stierhof, York-Dieter, Caffrey, Conor R, Steverding, Dietmar
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810305/
https://www.ncbi.nlm.nih.gov/pubmed/17328798
http://dx.doi.org/10.1186/1475-9292-6-2
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author Scory, Stefan
Stierhof, York-Dieter
Caffrey, Conor R
Steverding, Dietmar
author_facet Scory, Stefan
Stierhof, York-Dieter
Caffrey, Conor R
Steverding, Dietmar
author_sort Scory, Stefan
collection PubMed
description BACKGROUND: Current chemotherapy of human African trypanosomiasis or sleeping sickness relies on drugs developed decades ago, some of which show toxic side effects. One promising line of research towards the development of novel anti-trypanosomal drugs are small-molecule inhibitors of Trypanosoma brucei cysteine proteinases. RESULTS: In this study, we demonstrate that treatment of T. brucei-infected mice with the inhibitor, carbobenzoxy-phenylalanyl-alanine-diazomethyl ketone (Z-Phe-Ala-CHN(2)), alters parasite morphology and inhibits cell division. Following daily intra-peritoneal administration of 250 mg kg(-1 )of Z-Phe-Ala-CHN(2 )on days three and four post infection (p.i.), stumpy-like forms with enlarged lysosomes were evident by day five p.i. In addition, trypanosomes exposed to the inhibitor had a 65% greater protein content than those from control mice. Also, in contrast to the normal 16% of parasites containing two kinetoplasts – a hallmark of active mitosis, only 4% of trypanosomes exposed to the inhibitor were actively dividing, indicating cell cycle-arrest. CONCLUSION: We suggest that inhibition of endogenous cysteine proteinases by Z-Phe-Ala-CHN(2 )depletes the parasite of essential nutrients necessary for DNA synthesis, which in turn, prevents progression of the cell cycle. This arrest then triggers differentiation of the long-slender into short-stumpy forms.
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spelling pubmed-18103052007-03-06 The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo Scory, Stefan Stierhof, York-Dieter Caffrey, Conor R Steverding, Dietmar Kinetoplastid Biol Dis Original Research BACKGROUND: Current chemotherapy of human African trypanosomiasis or sleeping sickness relies on drugs developed decades ago, some of which show toxic side effects. One promising line of research towards the development of novel anti-trypanosomal drugs are small-molecule inhibitors of Trypanosoma brucei cysteine proteinases. RESULTS: In this study, we demonstrate that treatment of T. brucei-infected mice with the inhibitor, carbobenzoxy-phenylalanyl-alanine-diazomethyl ketone (Z-Phe-Ala-CHN(2)), alters parasite morphology and inhibits cell division. Following daily intra-peritoneal administration of 250 mg kg(-1 )of Z-Phe-Ala-CHN(2 )on days three and four post infection (p.i.), stumpy-like forms with enlarged lysosomes were evident by day five p.i. In addition, trypanosomes exposed to the inhibitor had a 65% greater protein content than those from control mice. Also, in contrast to the normal 16% of parasites containing two kinetoplasts – a hallmark of active mitosis, only 4% of trypanosomes exposed to the inhibitor were actively dividing, indicating cell cycle-arrest. CONCLUSION: We suggest that inhibition of endogenous cysteine proteinases by Z-Phe-Ala-CHN(2 )depletes the parasite of essential nutrients necessary for DNA synthesis, which in turn, prevents progression of the cell cycle. This arrest then triggers differentiation of the long-slender into short-stumpy forms. BioMed Central 2007-02-28 /pmc/articles/PMC1810305/ /pubmed/17328798 http://dx.doi.org/10.1186/1475-9292-6-2 Text en Copyright © 2007 Scory et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Scory, Stefan
Stierhof, York-Dieter
Caffrey, Conor R
Steverding, Dietmar
The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo
title The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo
title_full The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo
title_fullStr The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo
title_full_unstemmed The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo
title_short The cysteine proteinase inhibitor Z-Phe-Ala-CHN(2 )alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo
title_sort cysteine proteinase inhibitor z-phe-ala-chn(2 )alters cell morphology and cell division activity of trypanosoma brucei bloodstream forms in vivo
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810305/
https://www.ncbi.nlm.nih.gov/pubmed/17328798
http://dx.doi.org/10.1186/1475-9292-6-2
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