KEAP1-Inhibiting Brush Polymers for Proteolysis-Resistant Peptide Delivery
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Solution Overview
Problem
Existing peptide-based therapeutics targeting the protein-protein interaction between Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and Kelch-like ECH-Associating protein 1 (Keap1) face challenges such as inefficiencies in cellular uptake, rapid digestion by proteases, and lack of specificity, limiting their clinical applicability.
Innovation Solution
Development of peptide-like polymers with sequences having 75% or greater identity to specific Nrf2-binding motifs, conjugated with brush polymers to enhance cellular permeability and resistance to proteolysis, allowing for improved pharmacokinetic properties and administration routes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If peptide-based therapeutics are used to target Keap1/Nrf2 interaction, then binding affinity to target is improved, but cellular uptake efficiency deteriorates
Solution Approach 1:
The patent changes the physical-chemical parameters of the therapeutic molecule by converting peptides into polymer conjugates with modified molecular weight, charge distribution, and hydrophobicity. This allows the molecule to maintain binding affinity while improving cellular uptake through optimized physicochemical properties
Solution Approach 2:
The patent creates composite structures by conjugating peptide therapeutics with polymer carriers. The resulting hybrid molecule combines the target-binding capability of the peptide with the cell-permeability advantages of the polymer, simultaneously achieving both binding affinity and cellular uptake efficiency
2Strength
If peptide-based therapeutics are used to target Keap1/Nrf2 interaction, then binding affinity to target is improved, but in vivo stability deteriorates
Solution Approach 1:
The patent creates composite structures by conjugating peptide therapeutics with polymer carriers. The resulting hybrid molecule combines the target-binding capability of the peptide with the target: The polymer component protects the peptide from proteolytic degradation while maintaining its binding affinity to Keap1, thereby improving in vivo stability
Solution Approach 2:
The patent changes the molecular parameters by conjugating peptides with polymers, increasing molecular weight and altering the peptide's susceptibility to proteases. This structural modification protects the therapeutic molecule from degradation while preserving its binding function
3Ease of operation
If small molecule inhibitors are used to inhibit Keap1/Nrf2 interaction, then ease of administration is improved, but specificity deteriorates
Solution Approach 1:
The patent optimizes the molecular parameters of peptide-based therapeutics by conjugating them with polymers, creating molecules with ideal size, charge, and hydrophobicity profiles. This enables the therapeutics to achieve oral availability while maintaining the high specificity of peptide binding to Keap1
Solution Approach 2:
The patent creates hybrid molecules that combine the high specificity of peptide binding with the pharmacokinetic advantages of small molecules. The polymer-conjugated peptide maintains precise target recognition while achieving systemic administration capability
Data Source
AI summary
In an aspect, the invention provides therapeutic agents comprising brush polymers that address challenges associated with conventional administration of free therapeutic peptides. In an embodiment, for example, the invention provides brush polymers incorporating one or more therapeutic peptides comprising a sequence having 75% or greater sequence identity with an 8 to 12 amino acid fragment of SEQ ID NO: 218 (MDLIDILWRQDIDLGVSREVFDFS). Therapeutic agents of the invention comprising brush polymers include high-density brush polymers including cross-linked brush polymers, brush block copolymers, and brush random copolymers. In an embodiment, brush polymers of the invention exhibit proteolysis-resistant characteristics and maintain their biological function during formulation and administration. The invention also includes methods of making and using therapeutic agents comprising brush polymers.