Chimeric Protein TNHH Thrombin Inhibition via Linker Design
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Solution Overview
Problem
Current chimeric proteins targeting cardio-cerebrovascular diseases, such as brain stroke, face limitations due to the inability of hirugen to bind to the catalytic site of thrombin, reducing their therapeutic efficacy.
Innovation Solution
A recombinant chimeric protein, TNHH, is developed with the structure Met-NIF-linker 1-FPRP-linker 2-hirugen, where linker 1 consists of 5-15 glycines and linker 2 is (GSGG)n, enhancing the protein's ability to target and inhibit thrombin activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hirugen is incorporated into the chimeric protein structure, then the protein can inhibit thrombin activity, but the hirugen cannot bind to the catalytic site region, reducing therapeutic efficacy
Solution Approach 1:
The patent introduces a binding peptide of fibrin as an intermediary component between NIF and hirugen. This peptide serves as a mediator that enables hirugen to effectively target and bind to the catalytic site region of thrombin, thereby enhancing the overall therapeutic efficacy while maintaining the chimeric protein structure
Solution Approach 2:
The patent applies local quality by specifically designing the binding peptide of fibrin to be located at a particular position within the chimeric protein structure. This localized modification allows the hirugen component to effectively interact with the catalytic site region of thrombin, improving binding affinity and therapeutic effect without requiring complete structural redesign
2Reliability
If a binding peptide of fibrin is incorporated into the recombinant NHH protein, then the inhibitory effect on thrombogenesis is improved, but the specific structure and composition of the binding peptide are not defined in prior art
Solution Approach 1:
The patent applies parameter changes by optimizing the length and composition of the binding peptide of fibrin within the chimeric protein structure. By systematically varying these parameters and evaluating their effects on thrombin binding and therapeutic efficacy, the invention identifies the optimal peptide configuration that maximizes the inhibitory effect on thrombogenesis while ensuring precise structural definition for manufacturing
Data Source
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AI summary
Provided is a chimeric protein comprising neutrophil inhibitory factor, the peptide FRRP specially recognizing the thrombin active site and hirugen. Also provided is a pharmaceutical composition comprising the chimeric protein, which can be used for treating or preventing cerebral injury and cerebral edema, inhibiting platelet aggregation etc.