Mixed Peptoid Synthesis for Antibacterial Stability
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Solution Overview
Problem
Current antibiotic compounds face challenges due to increasing drug resistance and poor pharmacokinetic properties of peptide-based drugs, such as stability, membrane permeability, bioavailability, and water solubility, limiting their effectiveness and leading to adverse side effects.
Innovation Solution
The development of a method to synthesize mixed peptoids containing lysine and arginine type monomers, using orthogonal protecting groups like Dde and Boc, allows for the creation of linear and cyclic peptoids with aromatic side chains, enhancing biological activity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide-based drugs are used to combat infections, then biological activity is achieved, but stability and pharmacokinetic properties deteriorate
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of peptides to create peptoids - specifically, moving side chains from the alpha-carbon to the nitrogen atom of the backbone. This structural parameter change confers proteolytic stability while maintaining biological activity, resolving the contradiction between activity and stability
Solution Approach 2:
The patent creates composite peptoid structures incorporating both lysine-type (amine) and arginine-type (guanidinium) monomers in specific sequences. This composite approach combines the benefits of different side chain functionalities to achieve both stability and enhanced biological activity
2Quantity of substance
If peptides are formulated with excipients, surfactants and co-solvents to improve water solubility, then water solubility is improved, but adverse side effects increase
Solution Approach 1:
The patent modifies the chemical parameters of the peptoid structure by incorporating aromatic side chains and balancing cationic (lysine/arginine) with hydrophobic residues. This intrinsic structural modification improves water solubility without requiring external excipients, thereby avoiding adverse side effects
3Speed
If all lysine-type chains are transformed into arginine-type chains to improve cell penetration, then cell penetration is improved, but sequence diversity is reduced
Solution Approach 1:
The patent applies local quality by selectively transforming only specific lysine-type chains to arginine-type chains at predetermined positions in the peptoid sequence, while leaving other lysine-type chains unchanged. This localized modification maintains sequence diversity and allows optimization of cell penetration at specific locations without compromising overall versatility
Solution Approach 2:
The patent segments the peptoid sequence into distinct regions with different functionalities - some segments contain arginine-type monomers for cell penetration, while other segments retain lysine-type monomers for structural diversity. This segmentation allows independent optimization of different functional requirements
Data Source
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AI summary
The invention relates to peptoids, derivatives and analogues thereof, and to methods of chemically synthesising such compounds. The invention relates to mixed peptoids, derivatives and analogues thereof comprising lysine and arginine type monomers, which may be linear or cyclic, and to their uses in therapy, for example as antimicrobial agents, and in methods for treating microbial infections.