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Principal Investigator: Christopher Akinleye Alabi
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $316,226
Funding agency: National Institute of General Medical Sciences
Project Summary
This study seeks to advance heterobifunctional degraders that induce targeted protein degradation through
the ubiquitin proteasome pathway. Typically, molecular degraders involve a ligand that recruits an E3
ubiquitin ligase and another that targets a protein of interest (POI), forming an E3:Degrader:POI ternary
complex, leading to POI ubiquitination and subsequent degradation by the 26S proteasome. Peptide-based
proteolysis targeting chimeras (PepTACs) offer distinct advantages over small molecule degraders for
targeting protein-protein interactions due to their specificity, manufacturability, ease of design, and expansive
binding surface area. However, due to challenges related to their limited cellular permeability and stability,
which is evident in the modest potencies (micromolar range) of recently reported PepTACs, structure-function
studies to improve their catalytic activity have not been investigated. We highlight a recent breakthrough
where we facilitate PepTAC transport at nanomolar concentrations into cells via lipid nanoparticles (LNPs),
establishing a robust platform for our proposed studies. We aim to explore the structural attributes of
PepTACs to improve their catalytic activity and enhance target protein degradation. Our hypothesis revolves
around modifying PepTAC structure and amphipathicity to improve degradation efficiency, leveraging prior
literature showing that small molecule degraders with enhanced ternary complex stability drive greater target
protein degradation rates. Our study comprises three key aims: the first focuses on identifying the optimal
location of the E3 ligand to create a PepTAC that promotes enhanced positive cooperativity and rapid
ubiquitination. The second aim investigates how PepTAC structure impacts LNP loading, stability, and
intracellular transport. Finally, our third aim proposes a universal strategy for LNP loading based on tuning
PepTAC lipophilicity to enhance LNP encapsulation and systemic stability. Achieving these aims would
unlock the potential of PepTACs as valuable tools for cell-specific targeted protein degradation and
broadening access to a valuable class of peptide-based protein degraders.
Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><26 S proteasome complex><26S ATP-Dependent Protease><26S ATP-Dependent Proteasome><26S Proteasome Complex><26S Proteosome><26S protease><26S proteasome><APF-1><ATP-Dependent Proteolysis Factor 1><Address><Area><Assay><Attention><Binding><Bioassay><Biodistribution><Biological Assay><Biology><Blood Serum><Cell Body><Cells><Chemicals><Circulation><Complex><DNA Molecular Biology><Data><Development><Development and Research><Dose><Drugs><E3 Ligase><E3 Ubiquitin Ligase><Effectiveness><Encapsulated><Endosomes><Esteroproteases><Face><Formulation><Goals><HMG-20><High Mobility Protein 20><Intracellular Transport><Investigation><Ligands><Ligase><Ligase Gene><Literature><Location><Macropain><Macroxyproteinase><Measures><Mediating><Medication><Metabolic Protein Degradation><Methods><Mice><Mice Mammals><Modality><Molecular><Molecular Biology><Molecular Interaction><Multicatalytic Proteinase><Murine><Mus><Outcome><Pathway interactions><Penetration><Peptidases><Peptide Hydrolases><Peptides><Performance><Permeability><Pharmaceutical Preparations><Position><Positioning Attribute><Prosome><Protac><Protease Gene><Proteases><Proteasome><Proteasome Endopeptidase Complex><Protein Turnover><Proteinases><Proteins><Proteolysis targeting chimeric><Proteolytic Enzymes><Proteosome><R & D><R&D><Receptosomes><Regulatory Protein Degradation><Reporting><Research><Serum><Specificity><Structure><Structure-Activity Relationship><Surface><Synthetases><System><Tail><Therapeutic><Thermodynamic><Thermodynamics><Toxic effect><Toxicities><Ubiquitilation><Ubiquitin><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Variant><Variation><amphiphilicity><assess effectiveness><chemical structure function><design><designing><determine effectiveness><developmental><drug/agent><effectiveness assessment><effectiveness evaluation><evaluate effectiveness><examine effectiveness><faces><facial><improved><in vivo><interest><lipid based nanoparticle><lipid nanoparticle><lipophilicity><manufacturability><manufacture><multicatalytic endopeptidase complex><nano particle delivery><nano-molar><nanomolar><nanoparticle delivered><nanoparticle delivery><novel><pathway><precision medicine><precision-based medicine><protein degradation><protein protein interaction><proteolysis targeting chimera><recruit><research and development><small molecule><structure function relationship><therapeutic agent development><therapeutic development><tool><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase><uptake>