Hughes Louise M, Covian Raul, Gribble Gordon W, Trumpower Bernard L
Department of Biochemistry, Dartmouth Medical School, 7200 Vail, Hanover, NH 03755, USA.
Biochim Biophys Acta. 2010 Jan;1797(1):38-43. doi: 10.1016/j.bbabio.2009.07.010. Epub 2009 Aug 4.
Atovaquone is a substituted 2-hydroxy-naphthoquinone used therapeutically against Plasmodium falciparum (malaria) and Pneumocystis pathogens. It acts by inhibiting the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. As the targeted pathogens have developed resistance to this drug there is an urgent need for new alternatives. To better understand the determinants of inhibitor binding in the ubiquinol oxidation pocket of the bc(1) complex we synthesized a series of hydroxy-naphthoquinones bearing a methyl group on the benzene ring that is predicted to interact with the nuclear encoded Rieske iron-sulfur protein. We have also attempted to overcome the metabolic instability of a potent cytochrome bc(1) complex inhibitor, a 2-hydroxy-naphthoquinone with a branched side chain, by fluorinating the terminal methyl group. We have tested these new 2-hydroxy-naphthoquinones against yeast and bovine cytochrome bc(1) complexes to model the interaction with pathogen and human enzymes and determine parameters that affect efficacy of binding of these inhibitors. We identified a hydroxy-naphthoquinone with a trifluoromethyl function that has potential for development as an anti-fungal and anti-parasitic therapeutic.
阿托伐醌是一种取代的2-羟基萘醌，用于治疗恶性疟原虫（疟疾）和肺孢子虫病原体。它通过与泛醇氧化口袋中的 Rieske 铁硫蛋白和细胞色素b相互作用，抑制细胞色素bc(1)复合物。由于目标病原体已对该药物产生耐药性，因此迫切需要新的替代药物。为了更好地理解抑制剂在bc(1)复合物泛醇氧化口袋中的结合决定因素，我们合成了一系列在苯环上带有甲基的羟基萘醌，预计该甲基会与核编码的 Rieske 铁硫蛋白相互作用。我们还试图通过将末端甲基氟化来克服一种强效细胞色素bc(1)复合物抑制剂（一种带有支链侧链的2-羟基萘醌）的代谢不稳定性。我们已针对酵母和牛细胞色素bc(1)复合物测试了这些新的2-羟基萘醌，以模拟与病原体和人类酶的相互作用，并确定影响这些抑制剂结合效力的参数。我们鉴定出一种具有三氟甲基官能团的羟基萘醌，它有开发成抗真菌和抗寄生虫治疗药物的潜力。
