基于胃蛋白酶抑制剂的恶性疟原虫血浆蛋白酶II选择性抑制剂

[Selective inhibitors of plasmepsin II from Plasmodium falciparum based on pepstatin].

作者信息

Rumsh L D, Mikhaĭlova A G, Mikhura I V, Prudchenko I A, Chikin L D, Mikhaleva I I, Kaliberda E N, Dergousova N I, Mel'nikov E E, Formanovskiĭ A A

机构信息

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow, 117997 Russia.

出版信息

Bioorg Khim. 2008 Nov-Dec;34(6):739-46. doi: 10.1134/s1068162008060034.

DOI:10.1134/s1068162008060034

PMID:19088746

Abstract

A number of new inhibitors of plasmepsin II (PlmII) from Plasmodium falciparum, one of the key factors of malarial parasite survival, were synthesized. The inhibitors are analogues of pepstatin with various variants of Ala residue substitutions. Effects of the inhibitors on human PlmII and cathepsin D were studied. Inhibition of PlmII by the substrate was found, which required the use of the modified Henderson method for the determination of inhibition constants. Two synthesized inhibitors were shown to exhibit a pronounced selectivity to PlmII (K(i) = 5.5 and 5 nM) in comparison with cathepsin D (K(i) = 230 and 3000 nM, respectively).

摘要

合成了多种来自恶性疟原虫的组织蛋白酶II（PlmII）新抑制剂，PlmII是疟原虫生存的关键因素之一。这些抑制剂是胃蛋白酶抑制剂的类似物，具有不同变体的丙氨酸残基取代。研究了这些抑制剂对人PlmII和组织蛋白酶D的作用。发现底物对PlmII有抑制作用，这需要使用改良的亨德森方法来测定抑制常数。与组织蛋白酶D（K(i)分别为230和3000 nM）相比，两种合成抑制剂对PlmII表现出明显的选择性（K(i) = 5.5和5 nM）。