Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, Maryland 20742, United States.
Information Systems Group, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, United States.
J Phys Chem B. 2022 Jul 14;126(27):5033-5044. doi: 10.1021/acs.jpcb.2c02868. Epub 2022 Jun 30.
The cyclin-dependent kinase (CDK5) forms a stable complex with its activator p25, leading to the hyperphosphorylation of tau proteins and to the formation of plaques and tangles that are considered to be one of the typical causes of Alzheimer's disease (AD). Hence, the pathological CDK5-p25 complex is a promising therapeutic target for AD. Small peptides, obtained from the truncation of CDK5 physiological activator p35, have shown promise in inhibiting the pathological complex effectively while also crossing the blood-brain barrier. One such small 24-residue peptide, p5, has shown selective inhibition toward the pathological complex in vivo. Our previous research focused on the characterization of a computationally predicted CDK5-p5 binding mode and of its pharmacophore, which was consistent with competitive inhibition. In continuation of our previous work, herein, we investigate four additional binding modes to explore other possible mechanisms of interaction between CDK5 and p5. The quantitative description of the pharmacophore is consistent with both competitive and allosteric p5-induced inhibition mechanisms of CDK5-p25 pathology. The gained insights can direct further in vivo/in vitro tests and help design small peptides, linear or cyclic, or peptidomimetic compounds as adjuvants of orthosteric inhibitors or as part of a cocktail of drugs with enhanced effectiveness and lower side effects.
周期蛋白依赖性激酶 (CDK5) 与其激活剂 p25 形成稳定的复合物，导致 tau 蛋白过度磷酸化，并形成斑块和缠结，这被认为是阿尔茨海默病 (AD) 的典型原因之一。因此，病理性 CDK5-p25 复合物是治疗 AD 的一个有前途的靶点。从小鼠 CDK5 生理激活剂 p35 截断得到的小肽，已被证明在有效抑制病理性复合物的同时，也能穿过血脑屏障。其中一种 24 个残基的小肽 p5，在体内对病理性复合物具有选择性抑制作用。我们之前的研究集中于计算预测的 CDK5-p5 结合模式及其药效团的特征，该模式与竞争性抑制一致。在之前工作的基础上，本文研究了另外四种结合模式，以探索 CDK5 与 p5 之间可能存在的其他相互作用机制。药效团的定量描述与 CDK5-p25 病理学的竞争性和别构 p5 诱导抑制机制一致。获得的见解可以指导进一步的体内/体外试验，并有助于设计小分子、线性或环状肽或肽模拟化合物作为正位抑制剂的辅助剂，或作为增强疗效和降低副作用的药物鸡尾酒的一部分。
