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REVIEW ARTICLE

Targeted protein degraders: Blood–brain barrier permeability and central nervous system exposure

Satinder Singh1,2* ,  Satish Kumar1 ,  Vyas M. Shingatgeri2 ,  Pratima Srivastava1
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1 Drug Metabolism and Pharmacokinetics, Aragen Life Sciences Limited, Hyderabad, Telangana, India
2 School of Biosciences, Apeejay Stya University, Gurugram, Haryana, India
Advanced Neurology 2025, 4(2), 5140 https://doi.org/10.36922/an.5140
Submitted: 14 October 2024 | Revised: 10 January 2025 | Accepted: 11 February 2025 | Published: 21 February 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Innovative approaches are essential for treating central nervous system (CNS) diseases that present severe neurological manifestations and low survival rates. Delivering chemical or biological molecules across the blood–brain barrier (BBB) at therapeutically effective concentrations to treat CNS pathologies is a significant challenge. The urgent need for novel treatments targeting disease-causing proteins has propelled targeted protein degraders (TPDs) into the spotlight. TPDs have emerged as promising therapeutics for the treatment of CNS proteinopathies, characterized by the accumulation of misfolded protein aggregates. Given their structural features, the BBB permeability and CNS bioavailability of TPDs may seem improbable. However, several TPDs have demonstrated measurable concentrations in cerebrospinal fluid and the brain. Understanding the mechanisms behind their permeability across the BBB could open new avenues for the development of more effective TPD-based therapies for CNS proteinopathies. This review explores the absorption, distribution, metabolism, and excretion properties of TPDs in relation to brain pharmacokinetic parameters. It also delves into the likely interactions of advanced-stage TPDs with drug transporters and possibilities of disruption-propelled versus B-B barrier permeability-driven CNS bioavailability. Finally, it provides critical insights into the BBB permeability aspects of TPDs, uncovering new dimensions for future research.

Graphical abstract
Keywords
Targeted protein degraders
Central nervous system diseases
Blood–brain barrier
Proteinopathies
Pharmacokinetics
Permeability mechanisms
Funding
None.
Conflict of interest
Satinder Singh, Satish Kumar, and Pratima Srivastava are employees of Aragen Life Sciences Limited. Vyas M. Shingatgeri is the Dean of the School of Biosciences at Apeejay Stya University. The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this article.
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Advanced Neurology, Electronic ISSN: 2810-9619 Print ISSN: 3060-8589, Published by AccScience Publishing
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