Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

Terry K. Smith; Arthur Crossman; John S. Brimacombe; Michael A. J. Ferguson

doi:10.1038/sj.emboj.7600456

Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

Terry K. Smith
, Arthur Crossman
, John S. Brimacombe
, Michael A. J. Ferguson

Research output: Contribution to journal › Article › peer-review

66 Citations (Scopus)

Abstract

It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.

Original language	English
Pages (from-to)	4701-4708
Number of pages	8
Journal	The EMBO Journal
Volume	23
Issue number	23
DOIs	https://doi.org/10.1038/sj.emboj.7600456
Publication status	Published - Nov 2004

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

De-N-acetylase
Glycosylphosphatidylinositols
Inositol acyltransferase
Mannosyltransferase
Trypanosoma

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10.1038/sj.emboj.7600456

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title = "Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness",

abstract = "It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.",

keywords = "De-N-acetylase, Glycosylphosphatidylinositols, Inositol acyltransferase, Mannosyltransferase, Trypanosoma",

author = "Smith, \{Terry K.\} and Arthur Crossman and Brimacombe, \{John S.\} and Ferguson, \{Michael A. J.\}",

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T1 - Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

AU - Smith, Terry K.

AU - Crossman, Arthur

AU - Brimacombe, John S.

AU - Ferguson, Michael A. J.

N1 - dc.publisher: Nature Publishing Group

PY - 2004/11

Y1 - 2004/11

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AB - It has been suggested that compounds affecting glycosylphosphatidylinositol (GPI) biosynthesis in bloodstream form Trypanosoma brucei should be trypanocidal. We describe cell-permeable analogues of a GPI intermediate that are toxic to this parasite but not to human cells. These analogues are metabolized by the T. brucei GPI pathway, but not by the human pathway. Closely related nonmetabolizable analogues have no trypanocidal activity. This represents the first direct chemical validation of the GPI biosynthetic pathway as a drug target against African human sleeping sickness. The results should stimulate further inhibitor design and synthesis and encourage the search for inhibitors in natural product and synthetic compound libraries.

KW - De-N-acetylase

KW - Glycosylphosphatidylinositols

KW - Inositol acyltransferase

KW - Mannosyltransferase

KW - Trypanosoma

U2 - 10.1038/sj.emboj.7600456

DO - 10.1038/sj.emboj.7600456

M3 - Article

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SN - 0261-4189

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SP - 4701

EP - 4708

JO - The EMBO Journal

JF - The EMBO Journal

IS - 23

ER -

Chemical validation of GPI biosynthesis as a drug target against African sleeping sickness

Abstract

UN SDGs

Keywords

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