Druggability of CRMP2 for Neurodegenerative Diseases.,ACS Chemical Neuroscience

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Druggability of CRMP2 for Neurodegenerative Diseases.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-21 , DOI: 10.1021/acschemneuro.0c00307
Rajesh Khanna _{1,

2,

3,

4} , Aubin Moutal ₁ , Samantha Perez-Miller ₁ , Aude Chefdeville ₁ , Lisa Boinon ₁ , Marcel Patek ₅

Affiliation

Collapsin response mediator proteins (CRMPs) are ubiquitously expressed phosphoproteins that coordinate cytoskeletal formation and regulate cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. Accumulating evidence has also demonstrated a key role for CRMP2 in trafficking of voltage- and ligand-gated ion channels. These functions are tightly regulated by post-translational modifications including phosphorylation and SUMOylation (addition of a small ubiquitin like modifier). Over the past decade, it has become increasingly clear that dysregulated post-translational modifications of CRMP2 contribute to the pathomechanisms of diverse diseases, including cancer, neurodegenerative diseases, chronic pain, and bipolar disorder. Here, we review the discovery, functions, and current putative preclinical and clinical therapeutics targeting CRMP2. These potential therapeutics include CRMP2-based peptides that inhibit protein–protein interactions and small-molecule compounds. Capitalizing on the availability of structural information, we identify druggable pockets on CRMP2 and predict binding modes for five known CRMP2-targeting compounds, setting the stage for optimization and de novo drug discovery targeting this multifunctional protein.

中文翻译：

CRMP2 对神经退行性疾病的成药性。

崩解蛋白反应介导蛋白 (CRMP) 是普遍表达的磷蛋白，可协调细胞骨架的形成并调节细胞分裂、迁移、极性和突触连接。 CRMP2 是五个家族成员中研究最多的，因其对微管蛋白异二聚体的亲和力和调节微管网络的功能而闻名。越来越多的证据也证明了 CRMP2 在电压门控离子通道和配体门控离子通道运输中的关键作用。这些功能受到翻译后修饰的严格调节，包括磷酸化和 SUMOylation（添加小的泛素样修饰剂）。在过去的十年中，越来越清楚的是，CRMP2 的翻译后修饰失调会导致多种疾病的病理机制，包括癌症、神经退行性疾病、慢性疼痛和双相情感障碍。在此，我们回顾了针对 CRMP2 的发现、功能以及当前假定的临床前和临床治疗方法。这些潜在的疗法包括抑制蛋白质-蛋白质相互作用的基于CRMP2的肽和小分子化合物。利用结构信息的可用性，我们识别了CRMP2上的可成药口袋，并预测了五种已知的CRMP2靶向化合物的结合模式，为针对这种多功能蛋白的优化和从头药物发现奠定了基础。

更新日期：2020-09-02

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