<br>线粒体 F1FO-ATP 合酶作为心肌缺血再灌注损伤靶点的水解活性：新型抑制剂的发现以及体外和体内评估,Journal of Medicinal Chemistry

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线粒体 F1FO-ATP 合酶作为心肌缺血再灌注损伤靶点的水解活性：新型抑制剂的发现以及体外和体内评估
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-11-09 , DOI: 10.1021/acs.jmedchem.3c01048
Panagiota-Efstathia Nikolaou ₁ , George Lambrinidis ₂ , Maria Georgiou ₂ , Dimitrios Karagiannis ₂ , Panagiotis Efentakis ₁ , Pavlos Bessis-Lazarou ₁ , Konstantina Founta ₁ , Stavros Kampoukos ₂ , Vasilis Konstantin ₂ , Carlos M Palmeira ₃ , Sean M Davidson ₄ , Nikolaos Lougiakis ₂ , Panagiotis Marakos ₂ , Nicole Pouli ₂ , Emmanuel Mikros _{2,

5} , Ioanna Andreadou ₁

Affiliation

F₁F_O-ATP 合酶是负责 ATP 产生的线粒体复合物。在心肌缺血期间，它会逆转其活性，水解 ATP 并导致能量不足和心脏损伤。我们旨在发现 ATP 水解的新型抑制剂，了解缺血（I） /再灌注（R）损伤中靶点的成药性。使用基于配体的虚拟筛选方法揭示了新的分子支架。在分离的小鼠心脏线粒体和 H9c2 细胞上测试了 55 种化合物的抑制活性。在合成 9 种新型衍生物的 hit-lead 过程中鉴定和优化了吡唑并 [3,4-c] 吡啶苗头结构。三种衍生物在体外显着抑制 ATP 水解，而在体内，它们减小了心肌梗死面积（IS）。新型化合物 31 在降低 IS 方面最有效，验证了抑制 F₁F_O-ATP 水解活性可以作为缺血期间心脏保护的靶点。对信号通路的进一步检查表明，心脏保护机制与缺血心肌中 ATP 含量增加以及 PKA 和磷酸化增加有关，导致细胞凋亡减少。

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Hydrolytic Activity of Mitochondrial F1FO-ATP Synthase as a Target for Myocardial Ischemia–Reperfusion Injury: Discovery and In Vitro and In Vivo Evaluation of Novel Inhibitors

F₁F_O-ATP synthase is the mitochondrial complex responsible for ATP production. During myocardial ischemia, it reverses its activity, hydrolyzing ATP and leading to energetic deficit and cardiac injury. We aimed to discover novel inhibitors of ATP hydrolysis, accessing the druggability of the target within ischemia(I)/reperfusion(R) injury. New molecular scaffolds were revealed using ligand-based virtual screening methods. Fifty-five compounds were tested on isolated murine heart mitochondria and H9c2 cells for their inhibitory activity. A pyrazolo[3,4-c]pyridine hit structure was identified and optimized in a hit-to-lead process synthesizing nine novel derivatives. Three derivatives significantly inhibited ATP hydrolysis in vitro, while in vivo, they reduced myocardial infarct size (IS). The novel compound 31 was the most effective in reducing IS, validating that inhibition of F₁F_O-ATP hydrolytic activity can serve as a target for cardioprotection during ischemia. Further examination of signaling pathways revealed that the cardioprotection mechanism is related to the increased ATP content in the ischemic myocardium and increased phosphorylation of PKA and phospholamban, leading to the reduction of apoptosis.

更新日期：2023-11-09

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