Potential application of thymidylate kinase in nucleoside analogue activation in Plasmodium falciparum.
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.
Cui
Huaqing
H
College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
Ruiz-Pérez
Luis M
LM
González-Pacanowska
Dolores
D
Gilbert
Ian H
IH
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015215:Zidovudine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000962:Antimalarials; D004791:Enzyme Inhibitors; D009705:Nucleosides; D011355:Prodrugs; D015215:Zidovudine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase