Peptide Tertiary Amide Synthesis for Protein Ligands
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Solution Overview
Problem
Current methods for creating large, high-quality combinatorial libraries of peptide-like oligomers struggle with restricted rotation about the carbonyl-Cα and Cα-nitrogen bonds, limiting protein interactions and affinity.
Innovation Solution
The development of peptide tertiary amides (PTAs) with restricted conformations, synthesized through a sub-monomer route using optically pure 2-bromo acids and primary amines, allowing for Cα- and N-substitutions and enabling high-affinity protein ligands.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If peptoid libraries are synthesized using standard protocols, then large combinatorial libraries can be created easily, but the molecules exhibit high conformational flexibility resulting in low protein binding affinity
Solution Approach 1:
The patent changes the chemical structure parameter by replacing the standard peptoid amide bond with a tertiary amide bond containing a methyl group at the nitrogen position. This structural modification restricts conformational flexibility while maintaining the ease of library synthesis through solid-phase chemistry, thereby improving protein binding affinity without sacrificing productivity
Solution Approach 2:
The invention creates a hybrid molecule combining features of peptides (conformational restriction through N-methylation) and peptoids (ease of synthesis, cell permeability). This composite structure achieves both high binding affinity and practical synthesizability for large combinatorial libraries
2Reliability
If N-methylated peptides are used, then cell permeability and stability are improved, but only methyl substituents can be used limiting library diversity
Solution Approach 1:
The patent creates a universal platform where the N-methylated tertiary amide backbone provides consistent cell permeability and stability, while the R1 and R2 substituents can be varied independently to create diverse libraries. This multi-functional design allows the same core structure to serve both stability and diversity requirements
3Ease of operation
If rotation about carbonyl-Cα and Cα-nitrogen bonds is allowed, then molecular flexibility is maintained, but entropic penalty increases limiting binding affinity
Solution Approach 1:
The patent changes the rotational barrier parameter by introducing the N-methyl group in the tertiary amide bond. This increases the energy difference between cis and trans amide bond isomers, effectively restricting rotation and reducing conformational flexibility. The result is lower entropic penalty upon binding while maintaining necessary molecular flexibility for target engagement
Data Source
AI summary
The present disclosure is directed to a novel class of peptide-like oligomers called peptide tertiary amides (PTAs) and a combinatorial library of PTAs along with synthetic routes for the preparation of large combinatorial libraries of these compounds. The peptide tertiary amides provide an exceptional source of high affinity and selective protein ligands that are useful as tools for biological research and as drug leads, among others.