Activatable Fibrin-Binding Probes for Active Thrombus Detection
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Solution Overview
Problem
Current methods fail to accurately distinguish between newly formed and mature blood clots, as existing imaging agents cannot differentiate between thrombi with active and inactive platelets, limiting effective thrombus detection and treatment.
Innovation Solution
A method involving linear polypeptide probes that cyclize in the presence of protein disulfide isomerase (PDI) on activated platelets, allowing for specific binding to fibrin and detection of active thrombus formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing imaging agents are used, then thrombus detection is possible, but the ability to differentiate between active and inactive thrombi is lost
Solution Approach 1:
The invention divides the thrombus detection problem into two separate detection targets: fibrin (present in all thrombi) and PDI (present only in active thrombi with activated platelets). By using a bivalent probe that can detect both markers simultaneously, the system segments the information about thrombus presence and thrombus activity into distinct detectable signals, allowing differentiation between active and inactive thrombi.
Solution Approach 2:
The bivalent probe acts as an intermediary molecule that bridges two detection functions: one arm binds to fibrin while the other arm binds to PDI. This intermediary structure allows simultaneous detection of both thrombus components, translating the biological difference between active and inactive thrombi into a detectable signal ratio that preserves thrombus activity information.
2Ease of operation
If linear polypeptide probes are used, then they can be administered easily, but they cannot bind specifically to fibrin until cyclized
Solution Approach 1:
The probe is administered in its linear form, which is stable and易于给药, but the specific fibrin-binding function is activated only after the preliminary cyclization action occurs in vivo. The cyclization process, catalyzed by PDI in active thrombi, transforms the linear probe into a cyclic structure that can specifically bind to fibrin, ensuring that binding specificity is achieved at the right time and location.
Solution Approach 2:
The probe undergoes a parameter change from linear to cyclic conformation through disulfide bond formation. This structural parameter change is catalyzed by PDI and results in the acquisition of fibrin-binding capability. The parameter change (linear→cyclic) is the key transition that enables specific thrombus targeting while maintaining ease of administration in the initial linear state.
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
Enables precise imaging and identification of active thrombus formation by converting linear polypeptides into cyclized forms that bind to fibrin, facilitating targeted treatment approaches.
Implementation Method 1
cyclization of the at least two disulfide moieties, the resulting cyclized polypeptide is capable of binding to fibrin
Implementation Method 2
X is a linear polypeptide comprising at least two disulfide moieties, wherein upon cyclization of the at least two disulfide moieties
Implementation Method 3
the resulting cyclized polypeptide is capable of binding to fibrin; detecting the presence of the reaction product of the compound of Formula (I) and a protein disulfide isomerase
Data Source
AI summary
Provided herein are methods for determining the presence or absence of active thrombus formation using a linear polypeptide that binds fibrin upon cyclization. Also provided are compounds comprising linear polypeptide probes that are cyclized in the presence of protein disulfide isomerase.