Cockburn Ingrid L, Boshoff Aileen, Pesce Eva-Rachele, Blatch Gregory L
Biol Chem. 2014 Nov 1;395(11):1353-62. doi: 10.1515/hsz-2014-0138.
Plasmodial heat shock protein 70 (Hsp70) chaperones represent a promising new class of antimalarial drug targets because of the important roles they play in the survival and pathogenesis of the malaria parasite Plasmodium falciparum. This study assessed a set of small molecules (lapachol, bromo-β-lapachona and malonganenones A, B and C) as potential modulators of two biologically important plasmodial Hsp70s, the parasite-resident PfHsp70-1 and the exported PfHsp70-x. Compounds of interest were assessed for modulatory effects on the steady-state basal and heat shock protein 40 (Hsp40)-stimulated ATPase activities of PfHsp70-1, PfHsp70-x and human Hsp70, as well as on the protein aggregation suppression activity of PfHsp70-x. The antimalarial marine alkaloid malonganenone A was of particular interest, as it was found to have limited cytotoxicity to mammalian cell lines and exhibited the desired properties of an effective plasmodial Hsp70 modulator. This compound was found to inhibit plasmodial and not human Hsp70 ATPase activity (Hsp40-stimulated), and hindered the aggregation suppression activity of PfHsp70-x. Furthermore, malonganenone A was shown to disrupt the interaction between PfHsp70-x and Hsp40. This is the first report to show that PfHsp70-x has chaperone activity, is stimulated by Hsp40 and can be specifically modulated by small molecule compounds.
疟原虫热休克蛋白70（Hsp70）伴侣蛋白是一类很有前景的新型抗疟药物靶点，因为它们在恶性疟原虫的生存和发病机制中发挥着重要作用。本研究评估了一组小分子（拉帕醇、溴-β-拉帕醌以及马龙加烯酮A、B和C）作为两种具有生物学重要性的疟原虫Hsp70（驻留寄生虫的PfHsp70-1和输出的PfHsp70-x）的潜在调节剂。评估了感兴趣的化合物对PfHsp70-1、PfHsp70-x和人Hsp70的稳态基础ATP酶活性以及热休克蛋白40（Hsp40）刺激的ATP酶活性的调节作用，以及对PfHsp70-x的蛋白质聚集抑制活性的调节作用。抗疟海洋生物碱马龙加烯酮A尤其令人感兴趣，因为发现它对哺乳动物细胞系的细胞毒性有限，并且表现出有效疟原虫Hsp70调节剂的理想特性。发现该化合物抑制疟原虫而非人Hsp70的ATP酶活性（Hsp40刺激的），并阻碍PfHsp70-x的聚集抑制活性。此外，马龙加烯酮A被证明会破坏PfHsp70-x与Hsp40之间的相互作用。这是首次报道PfHsp70-x具有伴侣蛋白活性，受Hsp40刺激且可被小分子化合物特异性调节。
