Integrative Design of ADAMTS Partial Agonists within a Multi-Hallmark Therapeutic Framework: The Beginning of Paving the Way Toward a Functional Cure for Neurodegenerative Disorders

Neurodegenerative diseases (NDDs) such as Alzheimer’s, Parkinson’s, and multiple sclerosis are marked by progressive neuronal dysfunction, synaptic disintegration, and structural instability. Central to their pathology is the dysregulation of extracellular matrix (ECM) remodeling and the onset of chronic neuroinflammation. Emerging evidence implicates aberrant activity of ADAMTS metalloproteinases—particularly ADAMTS-4 and ADAMTS-5—in driving pathological ECM degradation that triggers inflammatory cascades and neuronal loss. In parallel, a holistic, multi-target therapeutic paradigm is evolving that not only aims to halt disease progression but also to restore functional neural networks. This approach integrates immune modulation to recalibrate maladaptive inflammatory responses, morphological adjustments through neurotrophic and regenerative strategies, and the fine-tuning of ECM dynamics. A key innovation within this framework is the development of partial agonists targeting ADAMTS enzymes. Leveraging bioisosteric design and structural modeling, these agents are engineered to selectively modulate enzymatic activity, thereby mitigating harmful ECM degradation while preserving essential physiological processes. Complementary advances in drug delivery—such as nanoparticle encapsulation and prodrug formulations—address the challenge of blood-brain barrier penetration, ensuring sustained and targeted central nervous system exposure. Furthermore, state-of-the-art imaging modalities (including PET/MR and synaptic tracers) enable real-time, personalized monitoring of therapeutic efficacy, setting the stage for adaptive treatment regimens. Collectively, these convergent strategies promise to enhance neuronal resilience, stabilize synaptic networks, and ultimately translate into improved clinical outcomes for patients with debilitating neurodegenerative conditions.