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Advanced Neurology

REVIEW ARTICLE
Targeted protein degraders: Blood–brain barrier

permeability and central nervous system
exposure

1,2
Satinder Singh *, Satish Kumar , Vyas M. Shingatgeri , and
1
2
Pratima Srivastava 1
1 Drug Metabolism and Pharmacokinetics, Aragen Life Sciences Limited, Hyderabad, Telangana,
India
2 School of Biosciences, Apeejay Stya University, Gurugram, Haryana, India

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,
*Corresponding author: characterized by the accumulation of misfolded protein aggregates. Given their
Satinder Singh structural features, the BBB permeability and CNS bioavailability of TPDs may seem
(satinder.singh@aragen.com) improbable. However, several TPDs have demonstrated measurable concentrations
Citation: Singh S, Kumar S, in cerebrospinal fluid and the brain. Understanding the mechanisms behind their
Shingatgeri VM, and Srivastava P. permeability across the BBB could open new avenues for the development of more
Targeted protein degraders: Blood–
brain barrier permeability and effective TPD-based therapies for CNS proteinopathies. This review explores the
central nervous system exposure. absorption, distribution, metabolism, and excretion properties of TPDs in relation
Adv Neurol. 2025;4(2):54-79. to brain pharmacokinetic parameters. It also delves into the likely interactions of
doi: 10.36922/an.5140
advanced-stage TPDs with drug transporters and possibilities of disruption-propelled
Received: October 14, 2024 versus B-B barrier permeability-driven CNS bioavailability. Finally, it provides critical
1st revised: December 31, 2024 insights into the BBB permeability aspects of TPDs, uncovering new dimensions for
future research.
2nd revised: January 10, 2025
Accepted: February 11, 2025
Keywords: Targeted protein degraders; Central nervous system diseases; Blood–brain
Published online: February 21, barrier; Proteinopathies; Pharmacokinetics; Permeability mechanisms
2025
Copyright: © 2025 Author(s).
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution 1. Introduction
License, permitting distribution,
and reproduction in any medium, The central nervous system (CNS) druggability has been attributed to molecules with
provided the original work is a molecular weight ≤400 Da, log partition coefficient (P) between 1.5 and 2.7, ≤2
properly cited. hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs), ≤5 rotatable
Publisher’s Note: AccScience bonds, a total polar surface area (tPSA) of 60 – 70 Å, a net positive charge at pH 7 –
Publishing remains neutral with 8 and a negative base 10 logarithm of the acid dissociation constant (pKa) between 4
regard to jurisdictional claims in 1
published maps and institutional and 10. In addition, tertiary nitrogen groups improve blood–brain barrier (BBB)
2
affiliations. permeability efficiency. On the contrary, highly protein-bound molecules (≥99.5%),

Volume 4 Issue 2 (2025) 54 doi: 10.36922/an.5140