Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury,Journal of Medicinal Chemistry

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Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-12-19 , DOI: 10.1021/acs.jmedchem.3c01578
Gwangsu Shin ₁ , Soonsil Hyun ₁ , Dongwoo Kim ₁ , Yoonhwa Choi ₂ , Kyu Hong Kim ₃ , Dongmin Kim ₂ , Soie Kwon ₄ , Yon Su Kim _{4,

5,

6} , Seung Hee Yang _{5,

6} , Jaehoon Yu _{1,

2}

Affiliation

Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating α-helical amphipathic “bundle” peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondria-damaging agents. With a stronger affinity for CL compared with other IMM lipid components, CMP3013 exhibited high selectivity. Consequently, it protected cristae, reduced ROS production, and enhanced adenosine triphosphate (ATP) generation. In mouse models of acute kidney injury, a 1 mg/kg dose of CMP3013 demonstrated remarkable efficacy, highlighting its potential as a therapeutic agent for mitochondrial dysfunction-related disorders. Overall, CMP3013 represents a promising agent for mitigating mitochondrial dysfunction and associated diseases.

中文翻译：

含环己基丙氨酸的 α-螺旋两亲肽靶向心磷脂，挽救肾损伤中的线粒体功能障碍

线粒体功能障碍与退行性疾病有关，退行性疾病是由心磷脂 (CL) 诱导的线粒体内膜 (IMM) 嵴结构破坏引起的；因此，保护嵴和防止 CL 重塑提供了维持线粒体功能的有效策略。为了鉴定针对线粒体功能障碍的活性氧 (ROS) 阻断剂，筛选了含有环己胺的细胞穿透性 α-螺旋两亲“束”肽库。其中，CMP3013 选择性地与异常线粒体结合，保留被线粒体损伤剂受损的嵴结构。与其他 IMM 脂质成分相比，CMP3013 对 CL 具有更强的亲和力，表现出高选择性。因此，它可以保护嵴，减少 ROS 的产生，并增强三磷酸腺苷 (ATP) 的产生。在急性肾损伤小鼠模型中，1 mg/kg 剂量的 CMP3013 显示出显着的疗效，凸显了其作为线粒体功能障碍相关疾病治疗剂的潜力。总体而言，CMP3013 是一种有前途的减轻线粒体功能障碍和相关疾病的药物。

更新日期：2023-12-19

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