de Vries E, Stam J G, Franssen F F, Nieuwenhuijs H, Chavalitshewinkoon P, de Clercq E, Overdulve J P, van der Vliet P C
Laboratory for Physiological Chemistry, University of Utrecht, The Netherlands.
Mol Biochem Parasitol. 1991 Jul;47(1):43-50. doi: 10.1016/0166-6851(91)90146-w.
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.
无环腺苷类似物（S）-9-（3-羟基-2-膦酰甲氧基丙基）腺嘌呤[HPMPA]属于一类核苷类似物，最初被描述为对多种DNA病毒具有强效活性。我们研究了这类药物对培养的恶性疟原虫生长的影响。HPMPA（ID50 = 47 nM）在浓度比人细胞细胞毒性剂量低1000倍以上时观察到强烈抑制作用。3-脱氮-HPMPA的抑制作用更强（ID50 = 8 nM），而其他几种无环核苷则无效。在感染伯氏疟原虫的小鼠中，单次注射HPMPA可使寄生虫血症增加被阻断4-6天。重复给药在临床可行的剂量下可长时间阻断寄生虫生长。我们还测定了二磷酸化的HPMPA（HPMPApp）对几种纯化的疟原虫DNA聚合酶的抑制作用。恶性疟原虫和伯氏疟原虫的α样DNA聚合酶被抑制，IC50 = 40 microM，而恶性疟原虫的γ样DNA聚合酶对该药物的敏感性甚至高40倍。HPMPApp的抑制作用与dATP竞争，强烈表明疟原虫DNA聚合酶是这类核苷酸类似物的作用靶点。
