Macrocyclic Peptide Libraries with Diketone Linchpin Functionalization
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing methods for producing genetically-encoded macrocyclic peptides face challenges in introducing reactive groups under benign conditions, as they often require harsh chemicals or conditions that damage the integrity of the peptide or nucleic acid libraries, and existing functionalization methods are slow and inefficient.
Innovation Solution
A method involving the use of a diketone linchpin, such as 1,5-dichloropentanedion-2,4, to cross-link peptides and introduce 1,3-diketone groups, followed by reaction with hydrazines in benign aqueous conditions to form macrocyclic peptides with diverse pharmacophores, allowing for rapid and stable functionalization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If harsh chemicals or conditions are used to introduce reactive groups into macrocyclic peptides, then the introduction of pharmacophores is achieved, but the integrity of the peptide and nucleic acid libraries is damaged
Solution Approach 1:
The patent changes the chemical parameters of the reaction conditions by using benign aqueous conditions (pH 6.0, 37°C) instead of harsh chemicals, enabling the introduction of reactive groups while preserving library integrity
Solution Approach 2:
The patent uses a diketone linchpin as an intermediary molecule that facilitates the introduction of pharmacophores through bioorthogonal chemistry, acting as a bridge between the peptide and the reactive groups without requiring harsh conditions
2Ease of manufacture
If existing functionalization methods are used to introduce pharmacophores, then pharmacophores are introduced into macrocyclic peptides, but the process is slow and inefficient
Solution Approach 1:
The patent replaces slow, traditional chemical functionalization methods with bioorthogonal chemistry based on the inverse electron demand Diels-Alder reaction, which proceeds rapidly under physiological conditions without requiring harsh reagents or extended incubation times
3Adaptability or versatility
If redox active metals such as copper are used to modify azido or alkyne groups, then unnatural pharmacophores are introduced, but the integrity of nucleic acids is destroyed via radical oxidative processes
Solution Approach 1:
The patent avoids the harmful effects of redox active metals by using copper-free bioorthogonal chemistry, specifically the inverse electron demand Diels-Alder reaction between tetrazines and trans-cyclooctenes, which introduces unnatural pharmacophores without generating radical oxidative processes that would damage nucleic acids
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables the rapid and stable introduction of pharmacophores into macrocyclic peptides under biocompatible conditions, preserving the integrity of the peptide and nucleic acid libraries, and facilitating the creation of mixed libraries with identifiable pharmacophores through silent DNA barcodes.
Implementation Method 1
a reactive compound comprising reactive groups Y1, Y2 and Z, which are capable of forming covalent bonds with said polypeptide
Implementation Method 2
reaction with hydrazines in benign aqueous conditions to form macrocyclic peptides with diverse pharmacophores
Data Source
AI summary
A macrocyclic polypeptide bearing a pharmacophore is produced by reacting (i) a peptide with two reactive groups X1 and X2; and (ii) a reactive compound comprising reactive groups Y1, Y2 and Z, such that X1 forms a bond by reaction with Y1 and X2 forms a bond by reaction with Y2. Reactive group Z is then reacted with a compound bearing a pharmacophore R in benign aqueous conditions. The macrocycles may be displayed in a library, such as a phage display library, and used to biopan for affinity against a selected target.