Eldar-Finkelman Hagit, Eisenstein Miriam
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Curr Pharm Des. 2009;15(21):2463-70. doi: 10.2174/138161209788682253.
Phosphorylation by protein kinases is a central theme in biological systems. Aberrant protein kinase activity has been implicated in a variety of human diseases, therefore, modulation of kinase activity represents an attractive therapeutic approach for the treatment of human illnesses. Development and design of specific inhibitors for protein kinases thus became a major strategy in many drug discovery programs. Inhibition of protein kinase activity may be achieved by blocking the phosphorylation activity or by disrupting protein-protein interactions. Peptides that can mimic most truly these regulatory modes are favorite choice for protein kinase-targeting. Here we focus on important motifs regulating the protein kinase signaling network and described how they may be exploited for peptide drug design. Protein kinases are important regulators of most, if not all, biological processes. Their abnormal activity has been implicated as causal factors in many human diseases, including cancer, diabetes and neurodegenerative disorders [1-3]. Protein kinases are thus attractive targets for drug design and compounds that manipulate their cellular activity are of enormous therapeutic potential. With a target in hand, medicinal chemists can generate low molecular weight compounds that bind the target with high affinity and alter its biological behavior. In many cases, however, drugs fail as they lack appropriate pharmaceutical properties and are of limited specificity resulting in unfavorable side effects. Under these circumstances, the use of peptides, which copy 'natural' motifs that specifically influence kinase activity and/or its intracellular interactions with cognate partners, may be a promising approach for selective inhibition of protein kinases. In this review we focus on the strategies to design such peptide inhibitors, focusing mainly on the serine/threonine protein kinase family.
蛋白激酶的磷酸化是生物系统中的一个核心主题。异常的蛋白激酶活性与多种人类疾病有关，因此，调节激酶活性是治疗人类疾病的一种有吸引力的治疗方法。因此，开发和设计蛋白激酶的特异性抑制剂成为许多药物研发项目中的主要策略。抑制蛋白激酶活性可以通过阻断磷酸化活性或破坏蛋白质-蛋白质相互作用来实现。能够最真实模拟这些调节模式的肽是靶向蛋白激酶的理想选择。在这里，我们重点关注调节蛋白激酶信号网络的重要基序，并描述如何将它们用于肽类药物设计。蛋白激酶是大多数（如果不是全部）生物过程的重要调节因子。它们的异常活性被认为是许多人类疾病的致病因素，包括癌症、糖尿病和神经退行性疾病[1-3]。因此，蛋白激酶是药物设计的有吸引力的靶点，能够操纵其细胞活性的化合物具有巨大的治疗潜力。有了靶点，药物化学家可以生成与靶点高亲和力结合并改变其生物学行为的低分子量化合物。然而，在许多情况下，药物会失败，因为它们缺乏合适的药物性质，特异性有限，会导致不良副作用。在这种情况下，使用能够复制特异性影响激酶活性和/或其与同源伴侣的细胞内相互作用的“天然”基序的肽，可能是选择性抑制蛋白激酶的一种有前途的方法。在这篇综述中，我们重点关注设计此类肽抑制剂的策略，主要聚焦于丝氨酸/苏氨酸蛋白激酶家族。
