Proximity-induced Pharmacology: A Novel Approach for Treating Amyloid-related Diseases

Raimon Galdeano^*
*Correspondence: Raimon Galdeano, Department of Medical Biotechnology, Soonchunhyang University, 22 Soonchunhyang-ro, Asan 31538, Republic of Korea, Email:

Introduction

Amyloid-related diseases, including Alzheimer's disease, Parkinson's disease, and type 2 diabetes, represent a significant global health burden with limited therapeutic options. The hallmark of these diseases is the accumulation of misfolded proteins, forming amyloid aggregates that disrupt cellular function and lead to tissue damage. Traditional pharmacological approaches often target these aggregates directly, aiming to dissolve or prevent their formation. However, these strategies have shown limited success in clinical trials, highlighting the need for alternative therapeutic approaches. Proximity-Induced Pharmacology (PIP) has emerged as a promising strategy to address the challenges associated with amyloid-related diseases. PIP leverages the proximity of pathological targets to modulate cellular processes indirectly, offering potential advantages over conventional approaches. This article provides an overview of PIP and its application in the treatment of amyloid-related diseases, discussing key concepts, mechanisms, and recent developments.

Description

Proximity-induced pharmacology exploits the spatial relationship between pathological targets and physiological processes within cells. Rather than directly interacting with the target, PIP agents engage with neighboring molecules or cellular components to influence target activity indirectly. This proximity-dependent modulation offers several advantages, including enhanced selectivity, reduced off-target effects, and improved therapeutic efficacy. Modulation of Protein-Protein Interactions: PIP agents can disrupt or enhance protein-protein interactions involved in amyloid aggregation processes. By altering the proximity of amyloidogenic proteins to chaperones or degradation machinery, PIP promotes the clearance of misfolded aggregates and prevents their accumulation.

PIP agents can modulate signaling pathways implicated in amyloidinduced toxicity. By targeting key nodes in these pathways, PIP restores cellular homeostasis and mitigates the deleterious effects of amyloid aggregates on neuronal function and viability. PIP agents can enhance cellular clearance mechanisms, such as autophagy and proteasomal degradation, to eliminate amyloidogenic proteins more efficiently. By promoting the degradation of misfolded aggregates, PIP reduces their cytotoxicity and attenuates disease progression. In Alzheimer's disease, the accumulation of Amyloid-Beta (Aβ) peptides and tau protein aggregates leads to synaptic dysfunction and neurodegeneration. PIP strategies targeting Aβ aggregation kinetics or tau pathology have shown promise in preclinical models, offering potential disease-modifying effects and cognitive benefits.

Parkinson's disease is characterized by the deposition of alpha-synuclein aggregates, known as Lewy bodies, in dopaminergic neurons. PIP approaches aimed at enhancing alpha-synuclein clearance or preventing its oligomerization hold therapeutic potential for slowing disease progression and preserving motor function. Type 2 diabetes is associated with the aggregation of amylin (islet amyloid polypeptide) in pancreatic islets, contributing to beta-cell dysfunction and insulin resistance. PIP strategies targeting amylin aggregation or enhancing beta-cell proteostasis offer novel therapeutic avenues for managing diabetes and preserving metabolic health.

Recent advances in PIP research have led to the identification of novel therapeutic targets and the development of innovative drug candidates for amyloid-related diseases. Integration of computational modeling, highthroughput screening, and advanced imaging techniques has facilitated the discovery of potent PIP agents with improved pharmacokinetic properties and target specificity. Future directions in PIP research include the exploration of combination therapies targeting multiple pathological processes simultaneously, personalized medicine approaches based on patient-specific molecular profiles, and the development of targeted drug delivery systems to enhance the efficacy and safety of PIP agents [1-5].

Conclusion

Proximity-induced pharmacology represents a promising approach for the treatment of amyloid-related diseases, offering unique advantages over conventional strategies. By leveraging the spatial relationship between pathological targets and cellular processes, PIP agents can modulate disease progression and restore cellular homeostasis effectively. Continued research and innovation in PIP are essential for translating preclinical discoveries into clinically meaningful therapies and addressing the unmet medical needs of patients with amyloid-related diseases.

Acknowledgement

None.

Conflict of Interest

None.

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