Targeting plasmodium falciparum purine salvage enzymes

A look at structure-based drug development

T. Donaldson, K. Kim

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

New antimalarials are needed due to the rapid development of resistance to currently deployed drugs. Because Plasmodium species are unable to synthesize purines, purine salvage pathways have been proposed as novel anti-malarial targets. The purine salvage pathway in Plasmodium is streamlined with adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and hypoxanthine-xanthine-guanine-phosphoribosyltransferase (HXGPRT) representing the major pathway for purine acquisition. Plasmodium falciparum enzymes PfADA and PfPNP have unique dual specificity that enable them to act upon methylthiopurines resulting from polyamine synthesis. Thus Plasmodium ADA and PNP function in both purine salvage and purine recycling. Genetic studies have confirmed the importance of Plasmodium PNP for viability of malaria parasites. Immucillins, powerful picomolar transition state inhibitors of PNP, are active against cultured Plasmodium falciparum and inhibit all Plasmodium PNPs tested. Several immucillins have undergone human clinical trials, and these compounds represent a new class of compounds with potential activity against human malarias.

Original languageEnglish (US)
Pages (from-to)191-199
Number of pages9
JournalInfectious Disorders - Drug Targets
Volume10
Issue number3
StatePublished - 2010

Fingerprint

Plasmodium
Purine-Nucleoside Phosphorylase
Plasmodium falciparum
Enzymes
Adenosine Deaminase
Pharmaceutical Preparations
Antimalarials
Malaria
Purines
Polyamines
Recycling
Human Activities
Parasites
purine
Clinical Trials

Keywords

  • Drug development
  • Immucillin
  • Malaria
  • Purine nucleoside phosphorylase
  • Purine salvage

ASJC Scopus subject areas

  • Molecular Medicine
  • Microbiology (medical)
  • Pharmacology

Cite this

Targeting plasmodium falciparum purine salvage enzymes : A look at structure-based drug development. / Donaldson, T.; Kim, K.

In: Infectious Disorders - Drug Targets, Vol. 10, No. 3, 2010, p. 191-199.

Research output: Contribution to journalArticle

@article{7bb18c25c0d3406f860d4db0aa864d36,
title = "Targeting plasmodium falciparum purine salvage enzymes: A look at structure-based drug development",
abstract = "New antimalarials are needed due to the rapid development of resistance to currently deployed drugs. Because Plasmodium species are unable to synthesize purines, purine salvage pathways have been proposed as novel anti-malarial targets. The purine salvage pathway in Plasmodium is streamlined with adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and hypoxanthine-xanthine-guanine-phosphoribosyltransferase (HXGPRT) representing the major pathway for purine acquisition. Plasmodium falciparum enzymes PfADA and PfPNP have unique dual specificity that enable them to act upon methylthiopurines resulting from polyamine synthesis. Thus Plasmodium ADA and PNP function in both purine salvage and purine recycling. Genetic studies have confirmed the importance of Plasmodium PNP for viability of malaria parasites. Immucillins, powerful picomolar transition state inhibitors of PNP, are active against cultured Plasmodium falciparum and inhibit all Plasmodium PNPs tested. Several immucillins have undergone human clinical trials, and these compounds represent a new class of compounds with potential activity against human malarias.",
keywords = "Drug development, Immucillin, Malaria, Purine nucleoside phosphorylase, Purine salvage",
author = "T. Donaldson and K. Kim",
year = "2010",
language = "English (US)",
volume = "10",
pages = "191--199",
journal = "Infectious Disorders - Drug Targets",
issn = "1871-5265",
publisher = "Bentham Science Publishers B.V.",
number = "3",

}

TY - JOUR

T1 - Targeting plasmodium falciparum purine salvage enzymes

T2 - A look at structure-based drug development

AU - Donaldson, T.

AU - Kim, K.

PY - 2010

Y1 - 2010

N2 - New antimalarials are needed due to the rapid development of resistance to currently deployed drugs. Because Plasmodium species are unable to synthesize purines, purine salvage pathways have been proposed as novel anti-malarial targets. The purine salvage pathway in Plasmodium is streamlined with adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and hypoxanthine-xanthine-guanine-phosphoribosyltransferase (HXGPRT) representing the major pathway for purine acquisition. Plasmodium falciparum enzymes PfADA and PfPNP have unique dual specificity that enable them to act upon methylthiopurines resulting from polyamine synthesis. Thus Plasmodium ADA and PNP function in both purine salvage and purine recycling. Genetic studies have confirmed the importance of Plasmodium PNP for viability of malaria parasites. Immucillins, powerful picomolar transition state inhibitors of PNP, are active against cultured Plasmodium falciparum and inhibit all Plasmodium PNPs tested. Several immucillins have undergone human clinical trials, and these compounds represent a new class of compounds with potential activity against human malarias.

AB - New antimalarials are needed due to the rapid development of resistance to currently deployed drugs. Because Plasmodium species are unable to synthesize purines, purine salvage pathways have been proposed as novel anti-malarial targets. The purine salvage pathway in Plasmodium is streamlined with adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and hypoxanthine-xanthine-guanine-phosphoribosyltransferase (HXGPRT) representing the major pathway for purine acquisition. Plasmodium falciparum enzymes PfADA and PfPNP have unique dual specificity that enable them to act upon methylthiopurines resulting from polyamine synthesis. Thus Plasmodium ADA and PNP function in both purine salvage and purine recycling. Genetic studies have confirmed the importance of Plasmodium PNP for viability of malaria parasites. Immucillins, powerful picomolar transition state inhibitors of PNP, are active against cultured Plasmodium falciparum and inhibit all Plasmodium PNPs tested. Several immucillins have undergone human clinical trials, and these compounds represent a new class of compounds with potential activity against human malarias.

KW - Drug development

KW - Immucillin

KW - Malaria

KW - Purine nucleoside phosphorylase

KW - Purine salvage

UR - http://www.scopus.com/inward/record.url?scp=77953857808&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953857808&partnerID=8YFLogxK

M3 - Article

VL - 10

SP - 191

EP - 199

JO - Infectious Disorders - Drug Targets

JF - Infectious Disorders - Drug Targets

SN - 1871-5265

IS - 3

ER -