Modified Cupredoxin Peptides for Extended Plasma Half-Life
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Solution Overview
Problem
Current pharmacologic agents, such as cupredoxin-derived peptides, face challenges with pharmacokinetic properties like short plasma half-life, susceptibility to biotransformation, and immunogenicity, which affect their efficacy and stability in treating conditions like cancer, viral infections, and malaria.
Innovation Solution
Modified cupredoxin-derived peptides with cyclization, thioether cyclization, and specific amino acid substitutions, such as replacing methionine with leucine or valine, and adding PEG molecules, to enhance stability, reduce biotransformation, and increase plasma half-life, while maintaining pharmacologic activities.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If cupredoxin-derived peptides are used for therapeutic treatment, then pharmacologic activity is achieved, but plasma half-life is short and biotransformation susceptibility is high
Solution Approach 1:
The patent applies parameter changes by modifying amino acid residues at specific positions (e.g., position 63, 64, 66, 67, 70, 71, 72, 73, 74, 75, 76, 77) to replace susceptible residues with more stable alternatives. This changes the chemical parameters of the peptide to resist biotransformation while maintaining pharmacologic activity, directly resolving the contradiction between short half-life and high biotransformation susceptibility.
Solution Approach 2:
The patent creates composite structures by combining cupredoxin-derived peptide sequences with stabilizing modifications, including disulfide bridge formations and PEGylation. These composite modifications enhance the peptide's stability against biotransformation while preserving its therapeutic pharmacologic activity, addressing the contradiction between short duration of action and high susceptibility to degradation.
2Reliability
If cupredoxin-derived peptides are used for therapeutic treatment, then pharmacologic activity is achieved, but immunogenicity is increased
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific positions within the peptide sequence rather than uniform modification throughout. This localized modification approach maintains the critical pharmacologic activity regions while altering immunogenic epitopes at specific locations, thereby preserving therapeutic efficacy while reducing immunogenicity.
Solution Approach 2:
The patent changes the chemical parameters of specific amino acid residues to modify immunogenic properties. By substituting residues at key positions with chemically similar but immunologically distinct alternatives, the patent reduces immunogenicity while maintaining the structural and functional parameters necessary for pharmacologic activity.
3Reliability
If amino acid substitutions are made to improve stability, then biotransformation resistance is increased, but structural integrity may be compromised
Solution Approach 1:
The patent carefully selects amino acid substitutions that change biotransformation resistance parameters while preserving structural integrity parameters. By choosing chemically similar amino acid alternatives (e.g., conservative substitutions) and testing specific position modifications, the patent achieves enhanced biotransformation resistance without compromising the overall structural stability and folding of the cupredoxin-derived peptide.
Solution Approach 2:
The patent employs feedback mechanisms by systematically evaluating the effects of amino acid substitutions on both biotransformation resistance and structural integrity. Through iterative testing and optimization of specific residue modifications, the patent identifies substitutions that provide the desired resistance to biotransformation while maintaining or enhancing structural stability, resolving the contradiction between these two parameters.
Data Source
AI summary
The present invention provides modified cupredoxin derived peptides with pharmacologic activity that have improved pharmacokinetic properties, and methods to use them to treat mammals suffering from various conditions related to the pharmacologic activities. Modifications of the cupredoxin derived peptides include amino acid sequence variants and structural derivations that increase the plasma half-life of the peptide, increase the specific activity of the pharmacologic activity, decrease immunogenicity, and decrease the biotransformation of the peptides. The modified cupredoxin derived peptides can be used in methods to treat mammals for cancer, conditions related to inappropriate angiogenesis, viral and bacterial infections, and specifically HIV and malaria, conditions related to ephrin signaling, and to deliver cargo compounds, including diagnostic compounds, to cancer cells.