Targeted Protein Degraders for Central Nervous System Drug Discovery: BBB Permeability, Pharmacokinetics, And Delivery Challenges

Abstract

Targeted protein degradation (TPD) has emerged as a promising strategy for eliminating disease-associated proteins that are difficult to modulate using conventional inhibitors. Among its major approaches, proteolysis-targeting chimeras (PROTACs) and molecular glue degraders have gained attention in neurodegenerative disease research. However, translating these degraders into effective central nervous system (CNS) therapies is challenging because the blood–brain barrier (BBB) restricts brain exposure and many degraders possess physicochemical and pharmacokinetic properties that are unfavourable for CNS delivery. This review examines the key factors governing CNS-targeted protein degradation, with emphasis on BBB permeability, molecular size, lipophilicity, polarity, hydrogen bonding, flexibility, brain exposure and unbound drug concentrations. Pharmacokinetic behaviour, PK–PD relationships and emerging delivery approaches, including nanocarriers, receptor-mediated transport, intranasal administration and exosome-based systems, are also discussed. In addition, in-silico strategies involving target and E3-ligase selection, ternary-complex modelling, molecular dynamics, BBB permeability and ADMET prediction are considered for early degrader optimization. Preclinical studies involving tau, ?-synuclein and DAPK1 demonstrate the potential of TPD in neurodegenerative disorders, although effective and selective degradation within the brain remains a major translational challenge. Overall, successful CNS protein degradation will require integrated optimization of degrader structure, brain exposure, pharmacokinetics, delivery and intracellular target engagement.

Keywords: Targeted protein degradation; PROTAC; molecular glue; central nervous system; blood–brain barrier; pharmacokinetics; CNS delivery; in-silico evaluation; neurodegenerative diseases