Bicyclic PD-L1 Peptide Ligands With High-Affinity Selective Binding
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Solution Overview
Problem
Existing cyclic peptides for targeting PD-L1 lack high affinity and specificity, leading to reduced efficacy in therapeutic applications.
Innovation Solution
Development of bicyclic peptides with specific amino acid sequences covalently bound to aromatic molecular scaffolds, forming multiple loops that enhance binding affinity and specificity to PD-L1.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If cyclic peptides are used to target PD-L1, then binding affinity is improved, but specificity is insufficient
Solution Approach 1:
The invention divides the single cyclic peptide structure into multiple peptide loops (at least two loops) that are independently tethered to a molecular scaffold. This segmentation allows each loop to contribute differently to binding, with some loops providing affinity and others providing specificity, thereby resolving the contradiction between binding strength and specificity.
Solution Approach 2:
The invention creates a composite structure combining multiple peptide sequences with distinct functions, tethered to a rigid molecular scaffold. The composite nature allows integration of different binding characteristics - one loop can be optimized for affinity while another loop provides specificity, achieving both high binding strength and specificity simultaneously.
2Manufacturing precision
If multiple peptide loops are tethered to a molecular scaffold, then binding specificity is improved, but structural complexity increases
Solution Approach 1:
The molecular scaffold serves multiple functions: it provides a rigid framework for positioning peptide loops, acts as a tethering point for multiple cysteine residues, and maintains the spatial arrangement necessary for specific binding. This multi-functionality reduces the need for additional complex structural elements, achieving high specificity without excessive complexity.
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 improved binding properties, stability, and selectivity, making them suitable for various administration routes and therapeutic applications.
Implementation Method 1
an aromatic molecular scaffold which forms covalent bonds with the cysteine residues of the polypeptide
Data Source
AI summary
Described herein are bicyclic peptides which are high affinity binders of programmed cell death 1 ligand 1 (PD-L1). Also provided are drug conjugates comprising the peptides described herein conjugated to one or more effector and/or functional groups. Also provided are pharmaceutical compositions comprising the peptides and drug conjugates described herein, and methods of using the peptide ligands and drug conjugates described herein for treating diseases mediated by PD-L1.