Research progress of PROTACs for neurodegenerative diseases therapy

Abstract

Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.

Keywords: Neurodegenerative disease; Protein degradation; Proteolytic targeting chimeras.