Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei by the DNA polymerase inhibitor HPMPA.
The acyclic adenosine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [HPMPA] belongs to a class of nucleoside analogues originally described as having potent activity against a broad spectrum of DNA viruses. We examined the effects of this class of drugs on the growth of cultured Plasmodium falciparum. Strong inhibition was observed by HPMPA (ID50 = 47 nM) at concentrations more than 1000-fold less than the cytotoxic dose for human cells. 3-deaza-HPMPA was even more strongly inhibitory (ID50 = 8 nM), whereas several other acyclic nucleosides were not effective. In mice infected with Plasmodium berghei, increase of parasitaemia can be blocked for 4-6 days by a single injection of HPMPA. Repeated drug administration blocks parasite growth for prolonged periods at doses that are clinically feasible. We also determined the inhibition of several purified Plasmodium DNA polymerases by diphosphorylated HPMPA (HPMPApp). DNA polymerase alpha-like enzymes of P. falciparum and P. berghei are inhibited with an IC50 = 40 microM and a gamma-like DNA polymerase from P. falciparum is even 40-fold more sensitive to the drug. The inhibition by HPMPApp is competitive with dATP, strongly suggesting that Plasmodium DNA polymerases are targets for this class of nucleotide analogue.
de Vries
E
E
Laboratory for Physiological Chemistry, University of Utrecht, The Netherlands.
Stam
J G
JG
Franssen
F F
FF
Nieuwenhuijs
H
H
Chavalitshewinkoon
P
P
de Clercq
E
E
Overdulve
J P
JP
van der Vliet
P C
PC
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D002460:Cell Line; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010962:Plasmodium berghei / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development*
D000981:Antiprotozoal Agents; D003838:Deoxyadenine Nucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D000225:Adenine