Modified BChE Enzyme Delivery for Ghrelin Inactivation
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Solution Overview
Problem
Ghrelin, a hormone involved in appetite regulation and metabolism, contributes to obesity and diabetes by activating the GHS-R receptor, and existing methods to inhibit its signaling are inadequate.
Innovation Solution
Administration of a polynucleotide encoding a modified butyrylcholinesterase (BChE) enzyme, such as SEQ ID NO: 5 or 6, to inactivate ghrelin by enhancing its ability to hydrolyze acyl ghrelin, using delivery vehicles like viral vectors or non-viral nanoparticles to target specific cells and tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing methods to inhibit ghrelin signaling are used, then ghrelin activity is reduced, but the methods are inadequate and do not achieve sufficient therapeutic effect
Solution Approach 1:
The patent modifies the BChE enzyme through amino acid substitutions (e.g., G117H, Y282N, G283H, T284M, P285L) to change its catalytic parameters and substrate specificity, enhancing its ability to hydrolyze acyl ghrelin. This parameter change in enzyme kinetics resolves the contradiction by making the enzyme more effective at its therapeutic function.
Solution Approach 2:
The patent uses BChE as an intermediary enzyme that mediates the inactivation of ghrelin. Rather than directly blocking the GHS-R receptor, the BChE enzyme acts as a mediator that cleaves the acyl group from ghrelin, rendering it inactive. This intermediary approach provides a more reliable and adaptable therapeutic mechanism.
2Productivity
If BChE is used to hydrolyze acyl ghrelin, then ghrelin inactivation is achieved, but the ability to effectively hydrolyze acyl ghrelin is insufficient with native BChE
Solution Approach 1:
The patent introduces specific amino acid substitutions in the BChE enzyme (such as G117H, Y282N, G283H, T284M, P285L) that change the kinetic parameters of the enzyme, specifically increasing its catalytic efficiency (kcat/Km) for acyl ghrelin substrates. This resolves the contradiction by simultaneously improving both the rate and reliability of hydrolysis.
Solution Approach 2:
The patent creates a modified BChE enzyme that combines the natural enzyme structure with specific mutational modifications, creating a composite catalytic system. This composite enzyme structure integrates the advantages of native BChE with enhanced substrate binding and catalytic capabilities, achieving both high productivity and reliability in ghrelin inactivation.
3Measurement precision
If delivery vehicles are used to target specific cells and tissues, then delivery precision is improved, but the system complexity increases
Solution Approach 1:
The patent uses delivery vehicles (viral vectors or non-viral nanoparticles) as intermediary carriers to transport the BChE enzyme or its encoding polynucleotide to target cells and tissues. These intermediaries provide targeting capabilities through surface ligands or tissue-specific tropism, achieving precise delivery without requiring complex surgical or mechanical systems.
Solution Approach 2:
The patent employs viral vectors that replicate and spread the BChE gene to target cells, or uses nanoparticle copies that can be mass-produced with standardized targeting moieties. This copying approach allows precise targeting to be achieved through replicated units rather than custom-designed complex systems for each application.
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
Inactivates ghrelin effectively, leading to reduced appetite and insulin resistance, potentially aiding in weight management and improving metabolic health.
Implementation Method 1
BChE has been shown to cleave the n-ocanoyl group and therefore inactivating ghrelin
Data Source
AI summary
Compositions and methods are provided for inactivating ghrelin in mammalian cells by administration of a polynucleotide encoding a butyrylcholinesterase (BChE) enzyme.