Hv1 Modulating Agents Using Phage Display Screening
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Solution Overview
Problem
There is a need for clinically compatible activators and inhibitors of voltage-gated proton channels (Hv1) due to their association with various physiological and pathological processes, but such modulators are currently not known.
Innovation Solution
The development of Hv1 modulating agents, including engineered polypeptide components with inhibitor cysteine knot (ICK)-like structural motifs, toxin sequence elements, and specific cysteine interactions, which can bind to the external surface of Hv1 channels and modulate their activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Hv1 modulating agents are developed to treat diseases associated with Hv1 channels, then therapeutic efficacy is improved, but the complexity of identifying clinically compatible modulators increases
Solution Approach 1:
The patent uses phage display technology to create a library of peptide copies that mimic potential Hv1 modulators. The phage-displayed peptides serve as copies of the desired modulating agents, allowing high-throughput screening to identify clinically compatible compounds without directly testing every possible chemical structure.
Solution Approach 2:
The patent introduces phage particles as intermediary carriers that display candidate peptide modulators on their surface. This intermediary system enables the peptides to be presented and screened in a standardized, high-throughput manner, simplifying the identification process while maintaining the ability to find effective Hv1 modulators.
2Reliability
If engineered polypeptide components with ICK-like motifs are used to modulate Hv1 channels, then binding affinity is improved, but the manufacturing complexity increases
Solution Approach 1:
The patent systematically varies parameters of the engineered polypeptides, including the specific cysteine residue positions, loop lengths, and amino acid sequences within the ICK-like framework. This parameter optimization allows the peptides to achieve high binding affinity to Hv1 channels while maintaining sequences that are relatively simple to synthesize and manufacture.
Solution Approach 2:
The patent focuses engineering efforts on specific local regions of the polypeptide structure, particularly the cysteine-rich ICK motif region, while keeping other portions of the sequence simpler. This localized optimization of critical binding regions achieves high affinity without requiring complex modifications throughout the entire molecule, thereby reducing manufacturing complexity.
Data Source
AI summary
The present invention provides novel agents for modulation of Hv1 channels. The present invention provides agents for activating and/or inhibiting Hv1 channel function and/or activity, and reagents and methods relating thereto.