Brush Polymer Peptide Conjugates for Proteolysis Resistance
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Solution Overview
Problem
Current peptide therapeutics targeting the Keap1/Nrf2 interaction face challenges with poor cell permeability and rapid digestion by proteases, limiting their clinical adoption and requiring complex administration methods.
Innovation Solution
Development of peptides with 11 to 16 amino acid residues showing 75% or greater sequence identity to LDEETGEFL, combined with a charge modulating domain, and conjugation to brush polymers for enhanced stability and cellular uptake, which are resistant to proteolysis and offer improved pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide therapeutics are used to target Keap1/Nrf2 interaction, then therapeutic efficacy is improved, but cell permeability is poor and rapid digestion by proteases occurs
Solution Approach 1:
The patent combines peptides with polymers to create composite conjugates. The peptide component maintains Keap1/Nrf2 binding activity while the polymer component provides proteolytic resistance and improved pharmacokinetic properties, resolving the contradiction between therapeutic efficacy and peptide stability.
Solution Approach 2:
The polymer acts as an intermediary carrier that protects the peptide from proteolytic degradation while maintaining its biological activity. This intermediary structure allows the peptide to circulate longer in the body without being rapidly digested, improving both stability and therapeutic efficacy.
2Adaptability or versatility
If peptide therapeutics are administered systemically, then treatment accessibility is improved, but cellular uptake is inefficient
Solution Approach 1:
The patent modifies the molecular weight and surface properties of the peptide-conjugate through polymer attachment, changing physical parameters to enhance cell permeability. This allows the therapeutic to be administered systemically while maintaining efficient cellular uptake through the modified pharmacokinetic properties.
3Stability of the object's composition
If chemical modification of amino acid sequence is used to protect from proteolysis, then peptide stability is improved, but multiple rounds of structure-function studies are required
Solution Approach 1:
Instead of modifying the peptide sequence directly, the patent uses a polymer as an intermediary protective layer. This approach achieves proteolytic resistance without requiring extensive structure-function studies to optimize amino acid modifications, as the polymer provides the protective function while the peptide maintains its original binding activity.
4Stability of the object's composition
If conjugation to pre-formed polymer or nanomaterial is used, then proteolytic resistance is improved, but additional conjugation and purification steps are required
Solution Approach 1:
The patent segments the therapeutic into distinct peptide and polymer components that can be independently optimized and then conjugated. This segmentation allows for modular manufacturing where the peptide and polymer are produced separately and then combined, simplifying the overall manufacturing process while maintaining proteolytic resistance.
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 of SEQ ID NO: 1 (LDEETGEFL) as side chain moieties. 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.