A long way to go: caspase inhibitors in clinical use.
A long way to go: caspase inhibitors in clinical use.
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DOI：
10.1038/s41419-021-04240-3
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发表时间：
2021-10-15
影响因子：
9
通讯作者：
Zhivotovsky B
中科院分区：
文献类型：
--
作者：
Dhani S;Zhao Y;Zhivotovsky B
半胱天冬酶是一个进化保守的半胱氨酸依赖性蛋白酶家族，参与许多重要的细胞过程，包括凋亡、增殖、分化和炎症反应。caspase介导的细胞凋亡和炎症的失调与多种疾病的发病机制有关，如炎症性疾病、神经系统疾病、代谢性疾病和癌症。多种半胱天冬酶抑制剂已被设计和合成，作为治疗细胞死亡相关病理的潜在治疗工具。然而，只有少数进入临床试验，因为用于治疗各种病理的不同类型的caspase抑制剂面临着一致的挑战，即疗效不足，靶点特异性差或不良副作用。重要的是，这种失败的很大一部分在于缺乏对各种caspase功能的理解。为了克服当前的挑战，进一步研究了解caspase在疾病模型中的功能是有效开发其抑制剂作为治疗不同病理的基本要求。因此，本文将重点介绍迄今为止已知的半胱天冬酶抑制剂的描述性质和特征，以及它们在动物和临床研究中的治疗应用。此外，本文还简要讨论了所取得的成就和当前面临的挑战，为进一步开发成功治疗各种疾病的caspase抑制剂提供了更多的视角。
Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.
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