First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness

Terry K Smith; Benjamin L. Young; Helen Denton; David L. Hughes; Gerd K. Wagner

doi:10.1016/j.bmcl.2009.01.083

First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness

Terry K Smith, Benjamin L. Young, Helen Denton, David L. Hughes, Gerd K. Wagner

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

Abstract

Drug-like molecules with activity against Trypanosoma brucei are urgently required as potential therapeutics for the treatment of African sleeping sickness. Starting from known inhibitors of other glycosyl-transferases, we have developed the first small molecular inhibitors of dolicholphosphate mannose synthase (DPMS), a mannosyltransferase critically involved in glycoconjugate biosynthesis in T. brucei. We show that these DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, and possess trypanocidal activity against live trypanosomes. (C) 2009 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	1749-1752
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	6
DOIs	https://doi.org/10.1016/j.bmcl.2009.01.083
Publication status	Published - 15 Mar 2009

Keywords

African sleeping sickness
Trypanosoma
Dolicholphosphate mannose synthase
Enzyme inhibitors
VARIANT SURFACE GLYCOPROTEIN
UDP-GALACTOPYRANOSE MUTASE
TRYPANOSOMA-BRUCEI
GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS
SELECTIVE INHIBITORS
ANTIGENIC VARIATION
IDENTIFICATION
DERIVATIVES
ROLES
GLYCOSYLTRANSFERASE

UN SDGs

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

Access to Document

10.1016/j.bmcl.2009.01.083

Cite this

@article{3502c8f6b3a346dfb395db69ce8a09a8,

title = "First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness",

abstract = "Drug-like molecules with activity against Trypanosoma brucei are urgently required as potential therapeutics for the treatment of African sleeping sickness. Starting from known inhibitors of other glycosyl-transferases, we have developed the first small molecular inhibitors of dolicholphosphate mannose synthase (DPMS), a mannosyltransferase critically involved in glycoconjugate biosynthesis in T. brucei. We show that these DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, and possess trypanocidal activity against live trypanosomes. (C) 2009 Elsevier Ltd. All rights reserved.",

keywords = "African sleeping sickness, Trypanosoma, Dolicholphosphate mannose synthase, Enzyme inhibitors, VARIANT SURFACE GLYCOPROTEIN, UDP-GALACTOPYRANOSE MUTASE, TRYPANOSOMA-BRUCEI, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS, SELECTIVE INHIBITORS, ANTIGENIC VARIATION, IDENTIFICATION, DERIVATIVES, ROLES, GLYCOSYLTRANSFERASE",

author = "Smith, {Terry K} and Young, {Benjamin L.} and Helen Denton and Hughes, {David L.} and Wagner, {Gerd K.}",

year = "2009",

month = mar,

day = "15",

doi = "10.1016/j.bmcl.2009.01.083",

language = "English",

volume = "19",

pages = "1749--1752",

journal = "Bioorganic and Medicinal Chemistry Letters",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness

AU - Smith, Terry K

AU - Young, Benjamin L.

AU - Denton, Helen

AU - Hughes, David L.

AU - Wagner, Gerd K.

PY - 2009/3/15

Y1 - 2009/3/15

N2 - Drug-like molecules with activity against Trypanosoma brucei are urgently required as potential therapeutics for the treatment of African sleeping sickness. Starting from known inhibitors of other glycosyl-transferases, we have developed the first small molecular inhibitors of dolicholphosphate mannose synthase (DPMS), a mannosyltransferase critically involved in glycoconjugate biosynthesis in T. brucei. We show that these DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, and possess trypanocidal activity against live trypanosomes. (C) 2009 Elsevier Ltd. All rights reserved.

AB - Drug-like molecules with activity against Trypanosoma brucei are urgently required as potential therapeutics for the treatment of African sleeping sickness. Starting from known inhibitors of other glycosyl-transferases, we have developed the first small molecular inhibitors of dolicholphosphate mannose synthase (DPMS), a mannosyltransferase critically involved in glycoconjugate biosynthesis in T. brucei. We show that these DPMS inhibitors prevent the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, and possess trypanocidal activity against live trypanosomes. (C) 2009 Elsevier Ltd. All rights reserved.

KW - African sleeping sickness

KW - Trypanosoma

KW - Dolicholphosphate mannose synthase

KW - Enzyme inhibitors

KW - VARIANT SURFACE GLYCOPROTEIN

KW - UDP-GALACTOPYRANOSE MUTASE

KW - TRYPANOSOMA-BRUCEI

KW - GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS

KW - SELECTIVE INHIBITORS

KW - ANTIGENIC VARIATION

KW - IDENTIFICATION

KW - DERIVATIVES

KW - ROLES

KW - GLYCOSYLTRANSFERASE

UR - http://www.scopus.com/inward/record.url?scp=61349199699&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2009.01.083

DO - 10.1016/j.bmcl.2009.01.083

M3 - Article

VL - 19

SP - 1749

EP - 1752

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 6

ER -

First small molecular inhibitors of T. brucei dolicholphosphate mannose synthase (DPMS), a validated drug target in African sleeping sickness

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this