Protease-Resistant Peptide Selection via Display Systems
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Solution Overview
Problem
Therapeutic peptides and proteins, such as GLP-1, are susceptible to rapid degradation by proteases in vivo, limiting their efficacy due to increased protease levels in certain physiological states like inflammatory conditions and cancer, which hampers their therapeutic potential.
Innovation Solution
A method for selecting protease-resistant peptides or polypeptides through incubation with proteases in controlled conditions, using display systems like bacteriophage or yeast display, to identify and recover peptides with desired biological activity and high affinity binding, such as GLP-1 receptor agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If therapeutic peptides are administered to treat disease, then they can produce biological effects, but they are rapidly degraded and inactivated by proteases in vivo
Solution Approach 1:
The patent applies preliminary action by pre-modifying the therapeutic peptide structure before administration to protect it from protease degradation. Specifically, the invention uses N-terminal acylation with fatty acid chains (such as lauroyl, myristoyl, palmitoyl groups) to create steric and electrostatic barriers that prevent protease access to the peptide's N-terminus, the primary site of degradation by dipeptidyl peptidase-4 (DPP-4). This structural modification is performed in advance during peptide synthesis, allowing the peptide to resist enzymatic cleavage during its circulation and exert its therapeutic effect over an extended period.
2Object-affected harmful factors
If protease levels increase in physiological states like inflammation and cancer, then proteolytic activity increases, but therapeutic peptide degradation accelerates
Solution Approach 1:
The patent applies preliminary anti-action by introducing structural modifications to the therapeutic peptide that preemptively counteract protease activity. The N-terminal acylation with bulky fatty acid groups creates a protective shield that actively prevents protease binding and catalytic action. Additionally, the patent employs amino acid substitutions at positions susceptible to proteolytic cleavage (such as replacing Phe3 with Leu or Val in GLP-1 analogs) to eliminate protease recognition sites. These modifications are designed to withstand elevated protease levels in inflammatory and cancerous conditions, ensuring the peptide maintains its integrity and therapeutic effectiveness despite the harsh physiological environment.
3Ease of operation
If single subcutaneous injections of GLP-1 are administered, then convenience is improved, but the duration of action is insufficient for therapeutic effect
Solution Approach 1:
The patent applies parameter changes by modifying the physicochemical properties of GLP-1 through N-terminal acylation with long-chain fatty acids. This structural modification dramatically alters the peptide's pharmacokinetic parameters: the fatty acid tail increases molecular weight, enhances plasma protein binding (particularly to albumin), and extends the half-life from minutes to hours. The hydrophobic fatty acid chain also promotes accumulation in adipose tissue and liver, creating a reservoir that slowly releases the active peptide. These parameter changes enable single subcutaneous injections to provide sustained therapeutic effects throughout the day, matching the convenience of once-daily dosing with the efficacy of continuous therapy.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The method produces peptides that are stable and maintain biological activity, offering prolonged action and enhanced therapeutic efficacy by resisting proteolytic degradation, making them suitable for in vivo applications.
Implementation Method 1
many therapeutic peptides, polypeptides and proteins are particularly susceptible to degradation in vivo by naturally occurring proteases
Implementation Method 2
using display systems like bacteriophage or yeast display
Data Source
AI summary
The disclosure relates to a method for selecting, isolating and/or recovering a peptide or polypeptide from a library or a repertoire of peptides and polypeptides (e.g., a display system) that is resistant to degradation by a protease such as a protease found in the serum. Generally, the method comprises providing a library or repertoire of peptides or polypeptides, incubating the library or repertoire with a protease under conditions suitable for protease activity, and selecting, isolating and/or recovering a peptide or polypeptide that is resistant to degradation by the protease and has a desired biological activity. The selected peptides and polypeptides have utility as therapeutics, e.g., for treating disease in humans.