Cyclic Peptides Targeting HIF-1α and HIF-2α PAS-B Domains
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Solution Overview
Problem
Current therapeutic approaches largely focus on targeting specific HIF-1α or HIF-2α isoforms individually, failing to effectively inhibit both isoforms simultaneously, which is crucial for addressing the hypoxic response in cancers where both isoforms contribute to tumour survival and growth.
Innovation Solution
Development of cyclic peptides that bind to the PAS-B domain of both HIF-1α and HIF-2α, inhibiting their interaction with HIF-1β, thereby disrupting hypoxia-response signaling, using a library of cyclic peptides optimized through structure-activity relationship data and incorporation of non-natural amino acids for enhanced potency and cell permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If selective targeting of one HIF isoform (HIF-1α or HIF-2α) is pursued, then specificity of inhibition is improved, but completeness of hypoxia-response blockade deteriorates
Solution Approach 1:
The cyclic peptide is designed to perform multiple functions by simultaneously targeting both HIF-1α and HIF-2α isoforms. The peptide sequence contains recognition elements that bind to conserved regions in both isoforms, enabling dual inhibition without requiring separate compounds for each target.
Solution Approach 2:
The invention merges the targeting capabilities into a single molecular entity that can recognize and bind to both HIF-1α and HIF-2α. By combining the essential binding motifs in one peptide sequence, the invention achieves comprehensive blockade of hypoxia-response pathways.
2Reliability
If cyclic peptides are optimized for potency through structure-activity relationship data and non-natural amino acids, then binding affinity to HIF isoforms is improved, but complexity of synthesis and characterization deteriorates
Solution Approach 1:
The peptide structure is optimized by systematically varying parameters such as amino acid sequence, cyclic constraints, and incorporation of non-natural amino acids. Structure-activity relationship studies guide these parameter changes to achieve optimal binding affinity while maintaining synthetic feasibility.
Solution Approach 2:
The use of non-natural amino acids allows for enhanced binding affinity by introducing chemically modified residues that can form additional interactions with the HIF isoforms. These modified amino acids serve as improved copies of natural residues with enhanced functional properties.
Data Source
AI summary
The invention provides cyclic peptides that are able to disrupt the typical response to hypoxia and which have particular utility in the treatment of cancers and von Hippel-Lindau disease.