Griffithsin Mutant Polypeptides for Oxidation Resistance and Solubility
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Solution Overview
Problem
Existing griffithsin compounds face challenges with methionine oxidation, reduced shelf-life, and limited solubility and bioavailability across different pH ranges, necessitating improved properties for effective viral inhibition.
Innovation Solution
Modified griffithsin polypeptides with specific mutations at positions 78, 75, 106, and 119, altering the isoelectric point to enhance solubility and bioavailability, and incorporating conjugates with effector components for targeted viral inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type griffithsin is used for viral inhibition, then antiviral activity is achieved, but methionine oxidation occurs reducing shelf-life
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues (Met61, Met78, Met116) to alternative residues (Val, Ala, Gly, Leu, Ile, Phe, Gln, Lys, Arg) to eliminate oxidation-prone methionine residues while preserving antiviral activity. This chemical parameter modification resolves the contradiction between maintaining reliability and extending duration.
Solution Approach 2:
The patent converts the harmful effect of methionine oxidation into a benefit by strategically replacing methionine residues with alternative amino acids that are either oxidation-resistant or have similar structural properties. This transforms the vulnerability into an opportunity to enhance shelf-life while maintaining or improving antiviral function.
2Reliability
If griffithsin is used for viral inhibition, then antiviral efficacy is achieved, but solubility is limited across different pH ranges
Solution Approach 1:
The patent modifies the isoelectric point of griffithsin through amino acid substitutions at positions 75, 106, and 119, which changes the protein's charge characteristics and solubility profile across different pH ranges. This parameter change enables the protein to maintain solubility in diverse physiological environments while preserving antiviral efficacy.
Solution Approach 2:
The patent applies local quality changes by introducing charged amino acid residues at specific positions (75, 106, 119) to create localized charge distributions that enhance overall solubility without disrupting the global structural integrity and antiviral function of the protein.
3Reliability
If griffithsin is used for viral inhibition, then antiviral activity is achieved, but bioavailability is limited across different pH environments
Solution Approach 1:
The patent changes the isoelectric point parameter through strategic amino acid substitutions to optimize the protein's charge state across different pH environments encountered in the body (stomach, intestine, blood, tissues). This enhances bioavailability by improving solubility and stability across the physiological pH range while maintaining antiviral activity.
Solution Approach 2:
The patent creates a universal griffithsin variant that functions effectively across multiple pH environments and biological compartments. The modified protein maintains antiviral activity whether encountered in acidic stomach conditions, neutral intestinal pH, or slightly alkaline blood pH, achieving multi-environment adaptability.
Data Source
AI summary
The invention provides modified griffithsin polypeptides comprising the amino acid sequence of SEQ ID NO: 1, as well as corresponding nucleic acids, vectors, cells, fusion proteins, constructs, conjugates, and methods of inhibiting viral infection.