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Design of Partial Agonists of ADAMTS Metalloproteinases as Therapeutics for Neurodegenerative Diseases
ChemRxiv Pub Date : 2025-01-03 , DOI: 10.26434/chemrxiv-2025-4n2nb David , Ferguson, MRSB MRSC
ChemRxiv Pub Date : 2025-01-03 , DOI: 10.26434/chemrxiv-2025-4n2nb David , Ferguson, MRSB MRSC
Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunction and structural instability, precipitated by aberrations in extracellular matrix (ECM) remodeling and chronic neuroinflammation. The ADAMTS family of metalloproteinases plays a key role in regulating ECM dynamics and neuroinflammatory responses, with dysregulation of specific isoforms contributing to the pathology of NDDs such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This article proposes the development of partial agonists targeting ADAMTS enzymes as a novel therapeutic approach for managing NDDs. By selectively modulating enzymatic activity, partial agonists could mitigate pathological ECM degradation while preserving essential protease functions. Structural scaffolds for partial agonist development are discussed, leveraging insights from bioisosteric design and computational methodologies. Additionally, advanced drug delivery platforms and preclinical validation paradigms are explored to address translational challenges. The integration of emerging technologies and modeling strategies is highlighted as a means to overcome current limitations and enhance the precision of ADAMTS-targeting therapies.
中文翻译:
ADAMTS 金属蛋白酶的部分激动剂作为神经退行性疾病治疗剂的设计
神经退行性疾病 (NDD) 的特征是进行性神经元功能障碍和结构不稳定,由细胞外基质 (ECM) 重塑和慢性神经炎症的畸变诱发。金属蛋白酶的 ADAMTS 家族在调节 ECM 动力学和神经炎症反应中起关键作用,特定亚型的失调会导致阿尔茨海默病、帕金森病和多发性硬化症等 NDD 的病理学。本文提出了开发靶向 ADAMTS 酶的部分激动剂作为管理 NDD 的新型治疗方法。通过选择性调节酶活性,部分激动剂可以减轻病理性 ECM 降解,同时保留基本的蛋白酶功能。讨论了用于部分激动剂开发的结构支架,利用生物等排设计和计算方法的见解。此外,还探索了先进的药物递送平台和临床前验证范式,以应对转化挑战。新兴技术和建模策略的整合被强调为克服当前限制和提高 ADAMTS 靶向疗法精度的一种手段。
更新日期:2025-01-03
中文翻译:
ADAMTS 金属蛋白酶的部分激动剂作为神经退行性疾病治疗剂的设计
神经退行性疾病 (NDD) 的特征是进行性神经元功能障碍和结构不稳定,由细胞外基质 (ECM) 重塑和慢性神经炎症的畸变诱发。金属蛋白酶的 ADAMTS 家族在调节 ECM 动力学和神经炎症反应中起关键作用,特定亚型的失调会导致阿尔茨海默病、帕金森病和多发性硬化症等 NDD 的病理学。本文提出了开发靶向 ADAMTS 酶的部分激动剂作为管理 NDD 的新型治疗方法。通过选择性调节酶活性,部分激动剂可以减轻病理性 ECM 降解,同时保留基本的蛋白酶功能。讨论了用于部分激动剂开发的结构支架,利用生物等排设计和计算方法的见解。此外,还探索了先进的药物递送平台和临床前验证范式,以应对转化挑战。新兴技术和建模策略的整合被强调为克服当前限制和提高 ADAMTS 靶向疗法精度的一种手段。