Cycloundecadepsipeptides for Cyclophilin Inhibition
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cyclophilin inhibitors, such as cyclosporin A, have significant immunosuppressive activity and poor aqueous solubility, limiting their therapeutic use due to adverse effects and formulation challenges.
Innovation Solution
Development of novel cycloundecadepsipeptides with reduced immunosuppressive activity and improved water solubility, specifically designed to bind cyclophilins like cyclophilin-A and cyclophilin-D, for treating cyclophilin-mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cyclosporin A is used as a cyclophilin inhibitor, then high binding affinity to cyclophilins is achieved, but immunosuppressive activity and adverse effects increase
Solution Approach 1:
The invention extracts and isolates the cyclophilin-binding function from the immunosuppressive activity by designing analogues that specifically target cyclophilin A without forming the ternary complex with calcineurin. The cycloundecadepsipeptide structure maintains nanomolar binding affinity to cyclophilin A while eliminating the immunosuppressive effect through selective inhibition of cyclophilin isomerase activity alone.
Solution Approach 2:
The patent applies local quality by modifying specific regions of the cyclosporin A molecule to create cycloundecadepsipeptides with altered properties. The structural modifications at specific positions (such as amino acid substitutions and cyclization) locally change the molecular characteristics to reduce immunosuppression while preserving cyclophilin binding capability.
2Reliability
If cyclosporin A is used as a cyclophilin inhibitor, then high binding affinity to cyclophilins is achieved, but aqueous solubility deteriorates
Solution Approach 1:
The invention changes the physicochemical parameters of the original cyclosporin A molecule by introducing polar groups, modifying amino acid residues, and creating cyclic structures that enhance water solubility. The cycloundecadepsipeptide analogues exhibit improved aqueous solubility through these parameter modifications while maintaining nanomolar binding affinity to cyclophilin A.
3Object-generated harmful factors
If structural modifications are made to reduce immunosuppression, then immunosuppressive activity is reduced, but binding affinity may deteriorate
Solution Approach 1:
The patent segments the molecular structure into critical regions for cyclophilin binding versus regions responsible for immunosuppressive activity. By selectively modifying the immunosuppression-related segments while preserving the binding-critical segments, the analogues achieve reduced immunosuppression with maintained nanomolar binding affinity to cyclophilin A.
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 cycloundecadepsipeptides effectively inhibit cyclophilins with reduced immunosuppressive properties and enhanced solubility, enabling their use in pharmaceutical compositions for treating various diseases without the adverse effects of existing inhibitors.
Implementation Method 1
novel cycloundecadepsipeptides which bind and inhibit cyclophilins, have reduced immunosuppressive activity and improved physicochemical properties
Data Source
AI summary
The present invention relates to novel cycloundecadepsipeptide compounds and their analogues which bind and inhibit cyclophilins, have reduced immunosuppressive activity and improved physicochemical properties including water solubility. The present invention further relates to pharmaceutical compositions containing said depsipeptide compounds and their analogues for use in the treatment or prevention of diseases and pathologies which may be ameliorated by the inhibition of cyclophilin activity.