Modified Cone Snail Polypeptide for Reduced Nav1.4 Inhibition
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Solution Overview
Problem
Existing μ-cone snail polypeptides used in cosmetics and pharmaceuticals cause facial muscle stiffness and paralysis due to excessive inhibition of skeletal muscle sodium channel Nav1.4, and inhibit myocardial and brain sodium channels, leading to adverse reactions.
Innovation Solution
A modified cone snail polypeptide with specific amino acid substitutions (SEQ ID NO: 1) is developed, which weakens the blocking effect on sodium channels while maintaining stability and target specificity, avoiding muscle stiffness and reducing the risk of inhibiting myocardial and brain channels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If μ-cone snail polypeptide is used to inhibit skeletal muscle sodium channel Nav1.4 for anti-wrinkle effect, then wrinkle reduction effect is improved, but facial muscle stiffness and paralysis occur
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the μ-cone snail polypeptide. Specifically, it changes the charge distribution and hydrophobicity parameters of the peptide through amino acid substitutions, which adjusts the binding affinity to Nav1.4 channels. This reduces excessive inhibition while maintaining sufficient anti-wrinkle effect, thereby resolving the contradiction between efficacy and muscle paralysis side effects
Solution Approach 2:
The patent applies local quality by making specific localized modifications to certain amino acid residues in the polypeptide sequence. These targeted changes at specific positions alter the interaction characteristics with the sodium channel while preserving the overall structure and function, enabling selective reduction of harmful effects on facial muscles while maintaining therapeutic benefit
2Reliability
If μ-cone snail polypeptide inhibits skeletal muscle and myocardial sodium channels, then strong muscle relaxation effect is achieved, but disturbance of normal membrane electrical signals and serious adverse reactions occur
Solution Approach 1:
The patent modifies key parameters including charge distribution, hydrophobicity, and molecular conformation through amino acid substitutions. These parameter changes selectively reduce the peptide's affinity for myocardial and brain sodium channels while preserving its ability to relax skeletal muscles, thus eliminating harmful side effects without sacrificing therapeutic effect
Solution Approach 2:
The patent converts the potentially harmful broad-spectrum channel blocking activity into a beneficial selective action. By carefully designing the modified sequence, the harmful inhibition of cardiac and neural channels is eliminated while the beneficial muscle relaxation effect is retained, effectively transforming a harmful property into a controlled beneficial one
Data Source
AI summary
The present disclosure belongs to the technical field of cosmetic preparation and provides a modified cone snail polypeptide, preparation method and use thereof. The amino acid residues are modified on the basis of the wild-type μ-cone snail polypeptide PIIIA, and the blocking effect of μ-cone snail polypeptide on sodium channels is moderately weakened, while maintaining stability under acidic and alkaline conditions and maintaining the stability of the isoelectric point and the target specificity. The modified cone snail polypeptide provided by the present disclosure has the characteristics of high stability and low production cost. The modified cone snail polypeptide after transformation and modification retains a strong anti-wrinkle function. The modified cone snail polypeptide avoids facial muscle stiffness and paralysis resulting from excessive inhibition of skeletal muscle sodium channel Nav1.4. At the same time, the use of modified cone snail polypeptide also significantly reduces the risk of inhibiting myocardial sodium channels and brain sodium channels, and modified cone snail polypeptide is readily absorbed through the membrane.