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Review
. 2023 Jun 26;12(3):43.
doi: 10.3390/antib12030043.

Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier

Toshihiko Tashima  1
Affiliations
Review

Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier

Toshihiko Tashima. Antibodies (Basel). .

Abstract

Drug development for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease has challenging difficulties due to the pharmacokinetic impermeability based on the blood-brain barrier (BBB) as well as the blurriness of pharmacodynamic targets based on their unclarified pathogenesis and complicated progression mechanisms. Thus, in order to produce innovative central nervous system (CNS) agents for patients suffering from CNS diseases, effective, selective delivery of CNS agents into the brain across the BBB should be developed. Currently, proteolysis-targeting chimeras (PROTACs) attract rising attention as a new modality to degrade arbitrary intracellular proteins by the ubiquitin-proteasome system. The internalizations of peptide-based PROTACs by cell-penetrating peptides and that of small molecule-based PROTACs through passive diffusion lack cell selectivity. Therefore, these approaches may bring off-target side effects due to wrong distribution. Furthermore, efflux transporters such as multiple drug resistance 1 (MDR1) expressed at the BBB might interrupt the entry of small molecule-based PROTACs into the brain. Nonetheless, intelligent delivery using machinery systems to absorb the nutrition into the brain for homeostasis, such as carrier-mediated transport (CMT) or receptor-mediated transcytosis (RMT), can be established. PROTACs with N-containing groups that are recognized by the proton-coupled organic cation antiporter might cross the BBB through CMT. PROTAC-antibody conjugates (PACs) might cross the BBB through RMT. Subsequently, such small molecule-based PROTACs released in the brain interstitial fluid would be transported into cells such as neurons through passive diffusion and then demonstrate arbitrary protein degradation. In this review, I introduce the potential and advantages of PROTAC delivery into the brain across the BBB through CMT or RMT using PACs in a non-invasive way.

Keywords: Alzheimer’s disease; NanoPROTAC; PROTAC; PROTAC-antibody conjugate; carrier-mediated transport; drug delivery into the brain; receptor-mediated transcytosis; tau protein degradation; the BBB; ubiquitin proteasome system.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
The structure of proteolysis-targeting chimeras (PROTACs) and the pathway of target protein degradation by PROTACs.
Figure 2
Figure 2
The pathway of intravenously administered PROTAC-antibody conjugates (PACs) against receptors (the light blue sphere) such as a transferrin receptor via a linker. PACs were internalized into the capillary endothelial cells.
Figure 3
Figure 3
The pathway of ubiquitin proteasome system. Abbreviations: E1, ubiquitin-activating enzyme; E2, ubiquitin conjugase; E3, ubiquitin ligase; Ub, ubiquitin; PP, diphosphoric acid.
Figure 4
Figure 4
The structures of X-protein and anti-X-protein PROTACs. The oligomerization domain (shown in red) acts as an X-protein ligand. The instability domain (shown in green) as a degron peptide acts as an E3 ligase ligand. Although R8 is a main cell-penetrating peptide (CPP) (shown in blue) in the molecule, X-entry is a type of CPP.
Figure 5
Figure 5
The structure of AP21998/ hypoxia inducible factor (HIF) 1α-based PROTAC, composed of AP21998 as a FK506 binding protein (FKBP12) ligand, the ALAPYIP sequence as a VHL ligand, and D-R8 as a cell-penetrating peptide (CPP), and dihydrotestosterone (DHT)/HIF 1α-based PROTAC, composed of DHT as an androgen receptor (AR) ligand, the ALAPYIP sequence as a VHL ligand, and D-R8.
Figure 6
Figure 6
The structures of TH006 with a VHL ligand, a tau ligand, and D-R8 as a cell-penetrating peptide (CPP), a peptide-based PROTAC with Kelch-like ECH-associated protein-1 (Keap1) ligand as an E3 ligase ligand, a tau ligand, and D-R8, and a peptide-based PROTAC with an α-synuclein ligand, an E3 ligase ligand, and TAT as a CPP.
Figure 7
Figure 7
The structures of the first proteolysis-targeting chimera (PROTAC) and the first small molecule-based PROTAC.
Figure 8
Figure 8
The structures of proteolysis-targeting chimeras (PROTACs) under clinical trials.
Figure 9
Figure 9
The structures of anti-tau PROTCs such as QC-01-175, C004019, and I3. The CLogP values were calculated by the software (ChemDraw Ultra version 7.0.1. provided from CambridgeSoft Corporation).
Figure 10
Figure 10
The structures of small molecule-based PROTACs for Parkinson’s disease (PD).
Figure 11
Figure 11
The structures of PROTACs for Huntington’s disease (HD).
Figure 12
Figure 12
The structure of trastuzumab-PROTAC conjugate with a BRD4 ligand and a VHL ligand.
Figure 13
Figure 13
The structure of anti-HER2 antibody-PROTAC conjugate with an ER ligand and a VHL ligand.
Figure 14
Figure 14
The structures of anti-STEAP1 antibody-PROTAC conjugates, STEAP1-5a and STEAP1-9d, with a BRD4 ligand and a VHL ligand.
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