Activatable Therapeutic Peptide Fusion Proteins for Disease-Site Release
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Solution Overview
Problem
Peptide therapeutics face challenges such as short circulation half-life, insufficient bioavailability at target sites, and off-target toxicity when administered systemically, particularly for membranolytic peptides like antimicrobial and anticancer peptides.
Innovation Solution
Development of fusion proteins comprising half-life extension compounds, anionic blocks, cleavable linkers, and therapeutic peptides, which are covalently linked to form long-circulating, masked therapeutic agents that activate at disease sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If therapeutic peptides are administered systemically, then they can reach target sites, but they exhibit short circulation half-life and insufficient bioavailability
Solution Approach 1:
The patent combines therapeutic peptides with serum albumin to form fusion proteins or conjugates. This merging of the peptide with the long-circulating albumin carrier extends the circulation half-life of the peptide while maintaining its therapeutic efficacy at target sites through the prolonged bloodstream residence time.
Solution Approach 2:
The invention creates composite structures where the therapeutic peptide is covalently linked or conjugated to albumin through specific linkers. This composite material combines the advantages of both components: the therapeutic activity of the peptide and the long circulation half-life of albumin, thereby improving bioavailability at target sites.
2Reliability
If membranolytic peptides are used to disrupt bacteria or cancer cell membranes, then therapeutic efficacy is achieved, but off-target toxicity occurs
Solution Approach 1:
The patent uses albumin as an intermediary carrier that delivers the membranolytic peptide to target sites. The albumin-peptide fusion protein or conjugate allows the peptide to remain inactive or less active during circulation, reducing off-target toxicity, while still achieving therapeutic efficacy when delivered to the intended target through the albumin-mediated delivery system.
Solution Approach 2:
The invention enables the therapeutic peptide to exhibit its membranolytic activity locally at the target site rather than systemically throughout the body. By conjugating the peptide to albumin, the therapeutic effect is concentrated at the disease site where the fusion protein accumulates, thereby maintaining efficacy while minimizing off-target toxicity.
3Adaptability or versatility
If therapeutic peptides are designed for systemic administration, then broader applicability is achieved, but short circulation half-life limits their utility
Solution Approach 1:
The patent merges the therapeutic peptide with albumin to create fusion proteins or conjugates that can be administered systemically. This combination allows the peptide to benefit from albumin's long circulation half-life and established pharmacokinetic properties, enabling effective systemic administration while maintaining the peptide's therapeutic versatility across different disease indications.
Data Source
AI summary
Disclosed herein are fusion protein, comprising (a) at least one X1 domain comprising a half-life extension compound, including but not limited to a half-life extension polypeptide; (b) at least one X2 domain comprising an anionic block; (c) at least one X3 domain comprising a linker susceptible to cleavage at a site of disease, including but not limited to a microbial infection site or tumor site; and (d) at least one X4 domain comprising a therapeutic peptide; wherein the at least one X1, X2, X3, and X4 domains are covalently linked, and each X4 domain is linked to an X3 domain without an intervening X1 or X2 domain; compositions containing such fusion proteins, and methods for their use.