Hotspot-Derived Peptide-Nucleic Acid Hybrids for Variant Neutralization
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Solution Overview
Problem
Existing antiviral strategies face challenges in maintaining effective binding to SARS-CoV-2 variants due to escape mutations, leading to reduced neutralization efficacy, necessitating the development of high-affinity reagents that can interact with both the original virus and its variants.
Innovation Solution
A method called Hotspot-Oriented Ligand Display (HOLD) is used to generate receptor-mimetic synthetic reagents by synergistically integrating hotspot peptides with nucleic acids, creating peptide-nucleic acid hybrids that maintain strong binding to the RBD of SARS-CoV-2 and its variants through in vitro evolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional affinity reagents are used to block virus-receptor interactions, then neutralization efficacy is achieved against wild-type virus, but binding affinity is lost against variant viruses due to escape mutations
Solution Approach 1:
The patent creates a hybrid molecule combining peptide and nucleic acid components. The peptide portion (hotspot-derived) provides high-affinity binding to the RBD, while the nucleic acid portion enables in vitro selection and amplification. This composite structure allows the reagent to maintain strong binding to both wild-type and variant viruses while enabling systematic optimization through selection processes.
Solution Approach 2:
The patent employs in vitro selection to iteratively optimize the peptide-nucleic acid hybrid molecules. Through multiple rounds of selection against different viral variants, the binding parameters (affinity, specificity) are continuously improved. This allows the reagent to adapt to variant mutations while maintaining or enhancing neutralization efficacy.
2Measurement precision
If affinity reagents target the hACE2 contact surface on the spike protein, then specific recognition is achieved, but neutralization efficacy is reduced when structural changes occur due to escape mutations
Solution Approach 1:
The patent performs in vitro selection against multiple viral variants in advance to pre-optimize the affinity reagents. By exposing the peptide-nucleic acid hybrids to variant RBDs during the selection process, the reagents are pre-adapted to recognize conserved epitopes that remain stable across variants, ensuring reliable neutralization efficacy despite structural changes.
Solution Approach 2:
The hotspot-derived peptide portion of the hybrid molecule is designed to bind to conserved regions of the RBD that are essential for receptor interaction. This universal binding approach allows a single reagent to recognize multiple variants while maintaining specific recognition of the virus-receptor interface.
3Adaptability or versatility
If antibody cocktails are co-administered to overcome escape mutations, then neutralization coverage is expanded, but resistance develops as variants accumulate more mutations
Solution Approach 1:
The patent employs in vitro selection where the peptide-nucleic acid hybrids themselves perform the selection process. The hybrids are subjected to iterative selection against viral variants, allowing them to self-optimize their binding properties. This self-service approach continuously improves variant coverage while maintaining reliable neutralization, as the selection process directly enriches for hybrids with robust cross-variant activity.
Data Source
AI summary
The present invention relates to a method for preparing an in vitro evolution-based hotspot-derived peptide-nucleic acid hybrid molecule. According to the method of the present invention, a hotspot-derived peptide-nucleic acid hybrid molecule that can bind with high affinity to viruses and effectively block the binding between the virus and the receptor can be rapidly prepared and screened in response to various virus mutations among numerous candidates. Therefore, it can be used very effectively for the development of therapeutics against various viral mutations.