Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
TA Instruments-Waters LLC, Shanghai, China.
Oxid Med Cell Longev. 2017;2017:9747296. doi: 10.1155/2017/9747296. Epub 2017 Nov 27.
(2S,3S,4S,5R,6R)-6-(4-((4-guanidinobutoxy)carbonyl)-2,6-dihydroxyphenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (ZYZ-488) was discovered as a novel inhibitor of apoptotic protease activating factor-1 (Apaf-1). In present work, a surface plasmon resonance (SPR) assay confirms the direct binding between ZYZ-488 and Apaf-1 and this interaction was found to be able to block the recruitment of procaspase-9 by Apaf-1. This study also shows that the treatment of MI (myocardial infarction) mice with this novel Apaf-1 inhibitor remarkably reduces the infarct size, improves cardiac functions, and attenuates the histopathology changes caused by MI. Meanwhile, here it is shown that ZYZ-488 decreases myocardial enzyme release, inhibits cardiomyocyte apoptosis, and suppresses the activation of the downstream cascade of caspases. Moreover, in silico prediction validated the drug-like properties of ZYZ-488. In conclusion, our findings present the first piece of evidence indicating the interaction between Apaf-1 and procaspase-9 as a novel therapeutic target in myocardial infarction and suggesting ZYZ-488 as a promising therapeutic option for myocardial infarction disease.
（2S，3S，4S，5R，6R）-6-（4-（（4-脒基丁氧基）羰基）-2,6-二羟基苯氧基）-3,4,5-三羟基四氢-2H-吡喃-2-羧酸（ZYZ-488）被发现是一种新型的凋亡蛋白酶激活因子-1（Apaf-1）抑制剂。在本研究中，表面等离子体共振（SPR）分析证实了 ZYZ-488 与 Apaf-1 之间的直接结合，并且这种相互作用能够阻止 procaspase-9 被 Apaf-1 招募。这项研究还表明，用这种新型 Apaf-1 抑制剂治疗心肌梗死（MI）小鼠可显著减少梗死面积，改善心脏功能，并减轻由 MI 引起的组织病理学变化。同时，研究结果表明，ZYZ-488 可降低心肌酶的释放，抑制心肌细胞凋亡，并抑制下游 caspase 级联的激活。此外，基于计算机的预测验证了 ZYZ-488 的类药性。总之，我们的研究结果提供了第一个证据，表明 Apaf-1 与 procaspase-9 之间的相互作用是心肌梗死的一个新的治疗靶点，并表明 ZYZ-488 是治疗心肌梗死的一种有前途的治疗选择。
