Ca2+/钙调素依赖性蛋白激酶II (CaMKII)靶向药物发现:挑战和策略。

IF 12.4 1区 医学 Q1 CELL BIOLOGY
Xinmiao Tian , Xianghui Wang , Sichong Chen , Xuefei Sun , Dongxue Shao , Kuo Zhang , Qinghua Gao , Liying Hao
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引用次数: 0

摘要

钙(Ca2+)/钙调蛋白(CaM)依赖性蛋白激酶II (CaMKII)是治疗年龄相关疾病的新兴药物靶点。它是一种多功能激酶,具有复杂的激活模式,众多的异构体,广泛的组织分布,在健康和疾病中起双重作用。特别是,它的同工异构体在催化和调节区域内具有高度的保守性,只有微小的差异局限于连接区域。CaMKII的这些特点使得选择性靶向抑制剂的开发尤其具有挑战性。目前的CaMKII抑制剂可分为以下几类:cam结合位点阻滞剂(KN62、KN93);atp竞争抑制剂(AS105、GS-680、RA306、RA608、SMP-114、NP202、橙皮苷);底物结合位点阻断剂(AIP, AC3-I, CN21);以及靶向通路的新型调节剂(例如,Athycaltide-1)。然而,目前还没有CaMKII抑制剂获得临床批准。然而,由于CaMKII在年龄相关病理中的关键作用,它仍然是一个引人注目的靶点。一些创新的方法有望克服当前的局限性,包括:通过蛋白水解靶向嵌合体(PROTACs)激活CaMKII的内源性降解,应用新材料,如肽或核酸为基础的药物和crispr - cas9介导的基因编辑方法,采用组织特异性传递系统和工程药物分子,以及靶向疾病特异性信号通路。总之,这些策略可能为更精确和有效的针对camkii的衰老相关疾病干预铺平道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ca2+/Calmodulin-dependent protein kinase II (CaMKII)-targeted drug discovery: Challenges and strategies
Calcium (Ca2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is an emerging drug target for age-related diseases. It is a multifunctional kinase with complex activation modes, numerous isoforms, broad tissue distribution, and a dual role in health and disease. In particular, its isoforms share a high degree of conservation within the catalytic and regulatory domains, with only minor differences confined to the linker region. These characteristics of CaMKII make the development of selectively targeted inhibitors particularly challenging. Current CaMKII inhibitors can be classified into the following categories: CaM-binding site blockers (KN62, KN93); ATP-competitive inhibitors (AS105, GS-680, RA306, RA608, SMP-114, NP202, hesperadin); substrate-binding site blockers (AIP, AC3-I, CN21); and pathway-targeted novel modulators (e.g., Athycaltide-1). However, no CaMKII inhibitor has yet reached clinical approval. Nevertheless, CaMKII remains a compelling target due to its pivotal role in age-related pathologies. Several innovative approaches hold promise for overcoming current limitations, including: activating endogenous degradation of CaMKII by proteolysis-targeting chimeras (PROTACs), applying novel materials such as peptide- or nucleic acid-based agents and CRISPR-Cas9-mediated gene editing approaches, employing tissue-specific delivery systems and engineered drug molecules, and targeting disease-specific signaling pathways. Together, these strategies may pave the way for more precise and effective CaMKII-targeted interventions in aging-associated diseases.
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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