Modified Nucleases Targeting Viral Nucleic Acids
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Solution Overview
Problem
Current antiviral agents face challenges such as high susceptibility to proteolytic degradation, low cellular uptake, short half-life, and the likelihood of viral resistance, while also failing to effectively target intermediate forms of viral nucleic acids during the replication cycle.
Innovation Solution
Development of chemically and genetically modified nucleases with enhanced hydrolytic activity, increased affinity for viral nucleic acids, and resistance to proteolytic degradation, which are designed to target specific forms of viral nucleic acids, including double-stranded DNA, single-stranded RNA, and RNA-DNA hybrids, using non-natural amino acids and polymeric carriers for improved stability and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native nucleases (DNase I, RNase A) are used to inhibit viral replication, then antiviral activity is achieved, but the nucleases are susceptible to proteolytic degradation and have short half-life
Solution Approach 1:
The patent modifies the chemical and physical parameters of nucleases through site-directed mutagenesis, introducing amino acid substitutions at specific positions (e.g., residues 1-10, 11-20, etc.) to enhance proteolytic stability while preserving hydrolytic activity against viral nucleic acids
Solution Approach 2:
The invention creates composite nuclease molecules combining modified protein sequences with polymeric carriers (e.g., polysaccharides, polymers) to form conjugates that provide both enzymatic activity and enhanced stability, protecting the nuclease from degradation while maintaining target specificity
2Reliability
If native nucleases are used for viral treatment, then some antiviral effect is observed, but cellular uptake is low and half-life is short
Solution Approach 1:
The patent modifies nuclease parameters through amino acid substitutions that enhance serum stability and extend half-life, while also optimizing cellular uptake properties through changes in surface charge and molecular structure
Solution Approach 2:
The invention uses polymeric carriers as intermediaries to deliver nucleases into cells, with the polymers facilitating cellular uptake and protecting the nuclease during circulation, thereby extending half-life and improving delivery efficiency
3Adaptability or versatility
If nucleases target only double-stranded DNA or single-stranded RNA, then specific viral forms are inhibited, but intermediate forms during replication cycle are not affected
Solution Approach 1:
The patent creates multi-functional nucleases or nuclease combinations that can hydrolyze multiple forms of viral nucleic acids (dsDNA, ssDNA, dsRNA, ssRNA, and intermediates) through engineered specificity, allowing a single agent or small combination to target various replication intermediates throughout the viral life cycle
Solution Approach 2:
The invention segments the viral replication cycle into different stages with distinct nucleic acid forms, and designs nucleases with specialized activity for each segment, using combinations of nucleases (e.g., DNase I variants, RNase A variants) to cover all forms from entry to assembly
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 modified nucleases demonstrate significantly increased hydrolytic activity and stability, effectively inhibiting viral replication by targeting multiple forms of viral nucleic acids, reducing the risk of viral resistance, and enhancing treatment efficacy.
Implementation Method 1
nucleases with hydrolytic activity towards a form of viral nucleic acid
Implementation Method 2
modified nuclease... greater hydrolytic activity than the parent nuclease
Data Source
AI summary
Antiviral compositions comprising a modified nuclease, or a plurality of such modified nucleases having at least one non-natural amino acid residue substituted for a naturally occurring amino acid in a parent nuclease are provided, as are methods of use and kits providing unit dosages of such compositions.