Potential application of thymidylate kinase in nucleoside analogue activation in Plasmodium falciparum

Huaqing Cui, Luis M. Ruiz-Perez, Dolores Gonzalez-Pacanowska, Ian H. Gilbert

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    Abstract

    Plasmodium falciparum thymidylate kinase (PfTMPK) shows a broad range of substrate tolerance when compared to the corresponding human enzyme. Besides 2'-deoxythymidine monophosphate (dTMP), PfTMPK can phosphorylate 3'-azido-2',3'-dideoxythymidine monophosphate (AZTMP) very efficiently. In contrast, human thymidylate kinase (hTMPK) is 200 times less active towards AZTMP. We were interested to see if we could use PfTMPK to activate 3'-azido-2',3'-deoxythymidine (AZT) derivatives as a strategy to treat malaria. P. falciparum lacks a pyrimidine nucleoside kinase which usually activates nucleoside and nucleoside analogues to the corresponding monophosphates. Therefore, several prodrug analogues of AZT and related nucleoside monophosphates were prepared and analysed for antiparasitic activity. The prodrugs showed an increase in activity over the parent nucleoside analogues, which showed no inhibition of parasite growth at the concentration tested. The evidence here reported provides a strategy that could be exploited for further anti-malarial design. (C) 2010 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)7302-7309
    Number of pages8
    JournalBioorganic & Medicinal Chemistry
    Volume18
    Issue number20
    DOIs
    Publication statusPublished - 15 Oct 2010

    Keywords

    • Malaria
    • Plasmodium
    • Thymidylate kinase
    • HEPATITIS-C VIRUS
    • INACTIVE NUCLEOSIDE
    • POLYMERASE-GAMMA
    • AZT
    • DRUGS
    • PHOSPHORYLATION
    • BETA
    • DERIVATIVES
    • TECHNOLOGY
    • INHIBITION

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