DR5 Domain Variant Fusion Protein for Low-Dose Infarction Protection
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Solution Overview
Problem
Current DR5 fusion proteins for treating myocardial infarction require high dosages, have limited administration routes, and do not effectively address myocardial cell ischemia and ischemia-reperfusion injury, with no specific therapeutic drugs available globally.
Innovation Solution
A DR5 domain variant with specific amino acid mutations and a fusion protein containing this variant, capable of binding TRAIL with high affinity, blocking apoptosis, and reducing infarction areas, which can be administered intracranially or intramuscularly, extending drug half-life and requiring lower doses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing DR5 fusion protein is used to treat myocardial infarction, then therapeutic effect is achieved, but high dosage is required
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (e.g., at positions 86-92, 105-112, 114-155) to the DR5 domain variant. These mutations alter the binding affinity and pharmacological properties of the fusion protein, enabling it to achieve therapeutic effects at lower dosages compared to the wild-type DR5 fusion protein.
2Reliability
If existing DR5 fusion protein is used, then therapeutic effect is achieved, but administration route is limited
Solution Approach 1:
The patent achieves universality by designing the DR5 domain variant fusion protein with enhanced pharmacokinetic properties that allow it to be administered through multiple routes (intracranial injection, intramuscular injection, intravenous infusion). The protein variant maintains therapeutic efficacy across different administration methods, providing clinical flexibility.
3Reliability
If existing DR5 fusion protein is used, then therapeutic effect is achieved, but frequent administration is required due to short half-life
Solution Approach 1:
The patent applies parameter changes by modifying the protein structure through amino acid mutations that enhance its pharmacokinetic stability. The variant DR5 domain fusion protein exhibits extended half-life in vivo, reducing the frequency of administration while maintaining consistent therapeutic effects.
4Object-affected harmful factors
If TRAIL-induced apoptosis pathway is blocked, then myocardial cell death is reduced, but no specific therapeutic drug is available
Solution Approach 1:
The patent uses the DR5 domain variant fusion protein as an intermediary substance that blocks the TRAIL-induced apoptosis pathway. The fusion protein acts as a soluble decoy receptor that competes with cell membrane DR5 for TRAIL binding, thereby preventing apoptosis without requiring endogenous DR5 expression.
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 fusion protein effectively protects against myocardial and cerebral infarction at lower doses, reduces infarction areas, and alleviates ischemia-reperfusion injury, with extended drug efficacy.
Implementation Method 1
capable of binding to TRAIL at a relatively high affinity
Implementation Method 2
blocking TRAIL/DR5 pathway-induced apoptosis
Implementation Method 3
reducing the area of myocardial infarction in cardiac ischemia and/or ischemia-reperfusion
Implementation Method 4
effectively extend the half-life of a drug in vivo
Data Source
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AI summary
The present application relates to a death receptor 5 (DR5) domain variant. The present application also relates to a fusion protein containing the DR5 domain variant. The fusion protein has one or more of the following properties: (1) being capable of binding to TRAIL; (2) blocking TRAIL/DR5 pathway-induced apoptosis; (3) reducing the area of myocardial infarction in cardiac ischemia and/or ischemia-reperfusion; and (4) having protective effects against cerebral infarction. The present application further provides a method for preparing the fusion protein, and the use thereof.