Bicyclic CD38 Peptide Ligands With Multi-Loop Binding Specificity
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Solution Overview
Problem
Existing cyclic peptides for targeting CD38 have limitations in binding affinity and specificity, particularly when multiple loops are involved, necessitating improved methods for generating high-affinity and selective peptide ligands.
Innovation Solution
Development of bicyclic peptides with at least three cysteine residues separated by loop sequences, covalently bound to a non-aromatic molecular scaffold, forming two loops, and conjugated with effector and/or functional groups to enhance binding and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cyclic peptides are used to target CD38, then binding affinity is improved, but binding specificity deteriorates
Solution Approach 1:
The invention divides the peptide structure into multiple separate loops (first loop, second loop, third loop) that are independently formed by cysteine residues. Each loop can independently interact with the CD38 target, allowing the overall structure to achieve both high affinity through multiple interaction points and high specificity through the unique spatial arrangement of these segmented loops on the molecular scaffold.
Solution Approach 2:
The invention creates different local structures by forming multiple distinct loops with specific amino acid sequences and lengths between cysteine residues. Each loop region has unique local properties that can be optimized for specific interactions with CD38, enabling the peptide to simultaneously achieve high binding affinity through cumulative interactions and high specificity through unique local recognition motifs.
2Reliability
If multiple loops are involved in CD38 targeting, then binding affinity is improved, but structural complexity increases
Solution Approach 1:
The molecular scaffold serves multiple functions simultaneously: it provides the structural framework for forming multiple loops, positions the cysteine residues to create the desired loop architecture, and maintains the overall structural integrity. This universal scaffold approach allows the peptide to achieve complex multi-loop structures for high binding affinity without proportionally increasing manufacturing complexity, as the scaffold provides a standardized platform.
3Measurement precision
If cysteine residues are covalently bound to molecular scaffold, then binding specificity is improved, but manufacturing complexity increases
Solution Approach 1:
The molecular scaffold is pre-designed and prepared before peptide synthesis, with reactive groups positioned to facilitate covalent bonding with cysteine residues. This preliminary preparation of the scaffold structure allows for streamlined manufacturing, as the covalent binding step becomes a standardized conjugation process rather than requiring complex in-situ formation of the multi-loop architecture during manufacturing.
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
The bicyclic peptides demonstrate superior CD38 competition binding and offer advantages such as species cross-reactivity, protease stability, desirable solubility, optimal plasma half-life, and selectivity over other CDs, making them suitable for various administration routes and therapeutic applications.
Implementation Method 1
a polypeptide comprising at least three cysteine residues, separated by at least two loop sequences, and a non-aromatic molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide
Data Source
AI summary
The present invention relates to polypeptides which are covalently bound to non-aromatic molecular scaffolds such that two or more peptide loops are subtended between attachment points to the scaffold. In particular, the invention describes peptides which are high affinity binders of CD38. The invention also includes drug conjugates comprising said peptides, conjugated to one or more effector and/or functional groups, to pharmaceutical compositions comprising said peptide ligands and drug conjugates and to the use of said peptide ligands and drug conjugates in preventing, suppressing or treating a disease or disorder mediated by CD38.