Peptidomimetic Macrocyclization Using Carbonyl Bioisosteric Turn-Inducing Elements
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for synthesizing cyclic peptide drugs face challenges such as low efficiency, C-terminal epimerization, cyclooligomerization, and side product formation, particularly in head-to-tail cyclization of short peptides, limiting the development of new macrocyclic scaffolds.
Innovation Solution
Incorporation of carbonyl bioisosteric turn-inducing elements, such as oxetanes, into the peptide backbone to facilitate cyclization by bringing the C- and N-termini into close proximity, enhancing yield and reducing byproducts, allowing for more efficient synthesis of peptidomimetic macrocycles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional head-to-tail cyclization methods are used for short peptides, then cyclization can be achieved, but the efficiency is low and multiple byproducts are formed
Solution Approach 1:
The patent introduces turn-inducing elements (such as pseudoproline, N-alkylated amino acids, or D-amino acids) as intermediary structures within the peptide backbone. These elements act as mediators that promote the cyclization reaction by inducing a turn in the peptide chain, bringing the N- and C-termini into closer proximity and facilitating macrocyclization while reducing byproduct formation
Solution Approach 2:
The patent modifies the peptide sequence by incorporating specific turn-inducing elements that change the conformational parameters of the peptide chain. This alters the spatial arrangement and proximity between terminal groups, enabling more efficient cyclization reactions with higher product purity
2Productivity
If multiple turn-inducing elements are incorporated to improve cyclization, then macrocyclization efficiency increases, but the peptide sequence requirements become more restrictive
Solution Approach 1:
The patent applies turn-inducing elements at specific local positions within the peptide sequence where they are most effective for inducing the necessary conformational turn. Rather than requiring multiple turn-inducing elements throughout the entire sequence, the invention identifies optimal locations that provide sufficient turn-inducing effect with minimal sequence restrictions
3Manufacturing precision
If the C-terminal epimerization is prevented, then product purity improves, but the synthesis complexity increases
Solution Approach 1:
The patent incorporates turn-inducing elements that preliminarily establish the correct stereochemistry and conformation during the cyclization process itself. By inducing a turn that brings terminal groups into proximity under controlled conditions, the method prevents C-terminal epimerization from occurring in the first place, rather than requiring separate steps to correct stereochemical issues
Data Source
AI summary
A method of macrocyclization of peptidomimetics is described which comprises substitution of one or more of the backbone amide C═O bonds with a turn-inducing motif. The method is general with enhancements seen across a range of ring sizes (e.g. tri-, tetra-, penta- and hexapeptides). Specifically, a peptidomimetic macrocycle is described comprising a carbonyl bioisosteric turn-inducing element having the structure:wherein X is a heteroatom; andwherein R1 to R6 are each independently selected from alkyl, aryl, heteroaryl and H.