Cyclized Peptide Monomer and Dimer Antagonists for Selective α4β7 Binding
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Solution Overview
Problem
Current integrin antagonists lack high affinity for α4β7 integrin and selectivity against α4β1 integrin, leading to side effects in treating gastrointestinal autoimmune diseases.
Innovation Solution
Development of novel peptidic compounds, including monomer and dimer peptides with cyclized structures, that exhibit high specificity and potency for α4β7 integrin, linked via C- or N-termini with suitable linker moieties, enhancing oral stability and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If current integrin antagonists are used, then they can bind to integrins, but they lack high affinity for α4β7 integrin and selectivity against α4β1 integrin, causing side effects
Solution Approach 1:
The patent applies local quality by designing peptides with specific local structural features (cyclized structures at N- or C-termini) that confer high affinity and selectivity for α4β7 integrin. The cyclic structure creates a rigid conformation that precisely fits the α4β7 binding site while excluding α4β1, thereby achieving high binding precision without off-target effects.
Solution Approach 2:
The patent changes key structural parameters of the integrin antagonist by introducing cyclized structures (N-terminal or C-terminal cyclic constraints) and optimizing amino acid sequences. These parameter changes transform the peptide from a flexible linear structure to a rigid cyclic structure, dramatically improving binding affinity for α4β7 and selectivity against α4β1, thereby eliminating side effects.
2Ease of manufacture
If linear peptides are used, then they are simple to synthesize, but they lack oral stability and therapeutic efficacy
Solution Approach 1:
The patent applies preliminary action by pre-forming cyclic structures at the N- or C-termini of the peptide during synthesis. This preliminary cyclization creates a stable rigid structure that protects the peptide from enzymatic degradation in the gastrointestinal tract, thereby ensuring oral stability while maintaining synthetic feasibility through standard cyclic peptide chemistry.
Solution Approach 2:
The patent creates composite structures by combining linear peptide sequences with cyclic structural elements. The hybrid architecture integrates the simplicity of linear peptide synthesis with the stability of cyclic structures, producing a compound that is both easy to manufacture and orally stable.
3Productivity
If high potency antagonists are developed, then they can effectively block integrin binding, but they may increase systemic exposure and cause side effects
Solution Approach 1:
The patent applies local quality by concentrating binding activity at specific local regions of the peptide (the cyclized terminal structures). These localized cyclic structures provide high-affinity binding to α4β7 integrin with picomolar potency, achieving maximum therapeutic efficacy at low doses and minimizing systemic exposure and side effects.
Data Source
AI summary
The invention relates to peptide dimer compounds and peptide monomer compounds that potently inhibit binding of α4β7 to the mucosal addressin cell adhesion molecule (MAdCAM) in vivo, possess high selectivity against α4β1 binding, and have high stability under gastrointestinal conditions.