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1,5‐Disubstituted‐1,2,3‐triazoles as inhibitors of the mitochondrial Ca 2+ ‐activated F 1 F O ‐ATP(hydrol)ase and the permeability transition pore
Annals of the New York Academy of Sciences ( IF 4.1 ) Pub Date : 2020-09-22 , DOI: 10.1111/nyas.14474
Vincenzo Algieri 1 , Cristina Algieri 2 , Loredana Maiuolo 1 , Antonio De Nino 1 , Alessandra Pagliarani 2 , Matteo Antonio Tallarida 1 , Fabiana Trombetti 2 , Salvatore Nesci 2
Affiliation  

The mitochondrial permeability transition pore (mPTP), a high-conductance channel triggered by a sudden Ca2+ concentration increase, is composed of the F1 FO -ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5-disubstituted 1,2,3-triazole derivatives, five-membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds 3a and 3b were selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+ -activated F1 FO -ATPase without affecting F-ATPase activity sustained by the natural cofactor Mg2+ . The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme-ATP complex. Both compounds show the same inhibition constant (K'i ), but compound 3a has a doubled inactivation rate constant compared with compound 3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+ -activated F1 FO -ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP-related diseases.

中文翻译:

1,5-二取代-1,2,3-三唑类作为线粒体 Ca 2+ 激活的 F 1 FO -ATP(水解)酶和渗透性转换孔的抑制剂

线粒体通透性转换孔 (mPTP) 是由 Ca2+ 浓度突然增加触发的高电导通道,由 F1 FO -ATPase 组成。由于 mPTP 开放导致线粒体功能障碍,这是许多疾病的特征,因此寻找 mPTP 调节剂是一个巨大的药理学挑战。在我们的研究中,研究了两个 1,5-二取代的 1,2,3-三唑衍生物、环中具有三个氮原子并能够与蛋白质形成次级相互作用的五元杂环的影响。在初步研究中,化合物 3a 和 3b 因其化学性质和有效性而在广泛的结构相关化合物中选择。在猪心线粒体中,两种化合物均抑制 Ca2+ 激活的 F1 FO-ATPase,而不会影响由天然辅因子 Mg2+ 维持的 F-ATPase 活性。抑制是相互排斥的,可能是因为它们共享酶位点,并且对 ATP 底物没有竞争性,因为它们只与酶-ATP 复合物结合。两种化合物都显示出相同的抑制常数 (K'i),但与化合物 3b 相比,化合物 3a 的灭活速率常数加倍。此外,这两种化合物都可以在不改变线粒体呼吸的情况下使 mPTP 开放脱敏。结果加强了 Ca2+ 激活的 F1 FO -ATPase 和 mPTP 之间的联系,并表明这些抑制剂可以在药理学上用于对抗 mPTP 相关疾病。并且对 ATP 底物没有竞争力,因为它们只与酶-ATP 复合物结合。两种化合物都显示出相同的抑制常数 (K'i),但与化合物 3b 相比,化合物 3a 的灭活速率常数加倍。此外,这两种化合物都可以在不改变线粒体呼吸的情况下使 mPTP 开放脱敏。结果加强了 Ca2+ 激活的 F1 FO -ATPase 和 mPTP 之间的联系,并表明这些抑制剂可以在药理学上用于对抗 mPTP 相关疾病。并且对 ATP 底物没有竞争力,因为它们只与酶-ATP 复合物结合。两种化合物都显示出相同的抑制常数 (K'i),但与化合物 3b 相比,化合物 3a 的灭活速率常数加倍。此外,这两种化合物都可以在不改变线粒体呼吸的情况下使 mPTP 开放脱敏。结果加强了 Ca2+ 激活的 F1 FO -ATPase 和 mPTP 之间的联系,并表明这些抑制剂可以在药理学上用于对抗 mPTP 相关疾病。
更新日期:2020-09-22
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