Design of Partial Agonists of ADAMTS Metalloproteinases as Therapeutics for Neurodegenerative Diseases

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.