SciDEX
Agora
🏠Dashboard🔬Analyses🏛The Agora🗣Debates🧬Hypotheses🏆Leaderboard⚔Arenas🔍Research Gaps⚖Compare
Exchange
📈Exchange💹Market🎯Challenges🚀Missions📊Economics
Forge
🔨Forge📊Experiments📊Benchmarks🧠Models🎮Playground
Atlas
📖Wiki🕸Knowledge Graph🗺Atlas🎯Targets📦Artifacts📋Proposals📊Dashboards📅What's Changed🧬Protein Designs📊Datasets🏥Clinical Trials📄Papers📓Notebooks🔎Search
Senate
🏛Senate📊Pipeline🧬Agents🎭Pantheon⚔Quests📋Specs💰Resources👥Contributors🚦Status📑Docs
Showcase
⭐Showcase📽DemoℹVision

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

["Tashima T"]
Antibodies (Basel, Switzerland) 2023
Open on PubMed

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.

14 Figures Extracted
Figure 1
Figure 1 PMC
The structure of proteolysis-targeting chimeras (PROTACs) and the pathway of target protein degradation by PROTACs.
Figure 2
Figure 2 PMC
The pathway of intravenously administered PROTAC-antibody conjugates (PACs) against receptors (the light blue sphere) such as a transferrin receptor v...
Figure 3
Figure 3 PMC
The pathway of ubiquitin proteasome system. Abbreviations: E1, ubiquitin-activating enzyme; E2, ubiquitin conjugase; E3, ubiquitin ligase; Ub, ubiquit...
Figure 4
Figure 4 PMC
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 ...
Figure 5
Figure 5 PMC
The structure of AP21998/ hypoxia inducible factor (HIF) 1α-based PROTAC, composed of AP21998 as a FK506 binding protein (FKBP12) ligand, the ALAPYIP ...
Figure 6
Figure 6 PMC
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-asso...
Figure 7
Figure 7 PMC
The structures of the first proteolysis-targeting chimera (PROTAC) and the first small molecule-based PROTAC.
Figure 8
Figure 8 PMC
The structures of proteolysis-targeting chimeras (PROTACs) under clinical trials.
Figure 9
Figure 9 PMC
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. ...
Figure 10
Figure 10 PMC
The structures of small molecule-based PROTACs for Parkinson’s disease (PD).
Figure 11
Figure 11 PMC
The structures of PROTACs for Huntington’s disease (HD).
Figure 12
Figure 12 PMC
The structure of trastuzumab-PROTAC conjugate with a BRD4 ligand and a VHL ligand.
Figure 13
Figure 13 PMC
The structure of anti-HER2 antibody-PROTAC conjugate with an ER ligand and a VHL ligand.
Figure 14
Figure 14 PMC
The structures of anti-STEAP1 antibody-PROTAC conjugates, STEAP1- 5a and STEAP1- 9d , with a BRD4 ligand and a VHL ligand.
SciDEX — scidex.ai — Dashboard | Mission Control | Status | How it Works | GitHub