Department of Applied Biology, Graduate School of Science and Technology, Kyoto Institute of Technology, Kyoto, Japan.
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Med Res Rev. 2019 Sep;39(5):1553-1602. doi: 10.1002/med.21560. Epub 2019 Jan 29.
The alternative oxidase (AOX) is a ubiquitous terminal oxidase of plants and many fungi, catalyzing the four-electron reduction of oxygen to water alongside the cytochrome-based electron transfer chain. Unlike the classical electron transfer chain, however, the activity of AOX does not generate adenosine triphosphate but has functions such as thermogenesis and stress response. As it lacks a mammalian counterpart, it has been investigated intensely in pathogenic fungi. However, it is in African trypanosomes, which lack cytochrome-based respiration in their infective stages, that trypanosome alternative oxidase (TAO) plays the central and essential role in their energy metabolism. TAO was validated as a drug target decades ago and among the first inhibitors to be identified was salicylhydroxamic acid (SHAM), which produced the expected trypanocidal effects, especially when potentiated by coadministration with glycerol to inhibit anaerobic energy metabolism as well. However, the efficacy of this combination was too low to be of practical clinical use. The antibiotic ascofuranone (AF) proved a much stronger TAO inhibitor and was able to cure Trypanosoma vivax infections in mice without glycerol and at much lower doses, providing an important proof of concept milestone. Systematic efforts to improve the SHAM and AF scaffolds, aided with the elucidation of the TAO crystal structure, provided detailed structure-activity relationship information and reinvigorated the drug discovery effort. Recently, the coupling of mitochondrion-targeting lipophilic cations to TAO inhibitors has dramatically improved drug targeting and trypanocidal activity while retaining target protein potency. These developments appear to have finally signposted the way to preclinical development of TAO inhibitors.
交替氧化酶 (AOX) 是植物和许多真菌中普遍存在的末端氧化酶，它与细胞色素电子传递链一起催化氧的四电子还原为水。然而，与经典的电子传递链不同，AOX 的活性不会产生三磷酸腺苷，但具有产热和应激反应等功能。由于它缺乏哺乳动物对应物，因此在致病真菌中进行了深入研究。然而，在缺乏细胞色素呼吸的感染阶段的非洲锥虫中，锥虫交替氧化酶 (TAO) 在其能量代谢中起着核心和重要作用。TAO 几十年前被验证为药物靶点，首批被确定的抑制剂之一是水杨羟肟酸 (SHAM)，它产生了预期的杀锥虫作用，尤其是与甘油联合使用以抑制厌氧能量代谢时更是如此。然而，这种组合的疗效太低，无法实际用于临床。抗生素 ascofuranone (AF) 被证明是一种更强的 TAO 抑制剂，能够在没有甘油的情况下并以更低的剂量治愈小鼠中的 Trypanosoma vivax 感染，这提供了一个重要的概念验证里程碑。系统地努力改进 SHAM 和 AF 支架，辅以 TAO 晶体结构的阐明，提供了详细的结构-活性关系信息，并重新激发了药物发现工作。最近，将靶向线粒体的亲脂性阳离子与 TAO 抑制剂偶联，显著提高了药物靶向性和杀锥虫活性，同时保留了靶蛋白效力。这些进展似乎终于为 TAO 抑制剂的临床前开发指明了方向。
