ProM-15 Polyproline Mimetics for Ena/VASP-EVH1 Binding
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Solution Overview
Problem
Current polyproline mimetics have suboptimal binding properties and stability issues, particularly in inhibiting Ena/VASP-EVH1-mediated protein-protein interactions, due to complex production processes and susceptibility to proteases, which limits their effectiveness as anticancer agents.
Innovation Solution
Development of novel polyproline mimetics, such as ProM-15 compounds with an 'east ring-opened' structure, that enhance binding affinity by increasing C-terminal flexibility and addressing hydrophobic binding pockets, while reducing molecular weight and improving stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptide compounds with adjacent diproline mimetics are used, then binding affinity to VASP-EVH1 domain is improved, but production complexity increases and stability against proteases deteriorates
Solution Approach 1:
The patent changes the chemical structure parameters by replacing peptide bonds with non-peptidic linkers (e.g., amide bonds, ether bonds) and modifying the diproline mimetic core structure. This transforms the compound from a peptide-based inhibitor to a small molecule inhibitor, thereby improving stability against proteases while maintaining binding affinity through optimized molecular recognition elements.
Solution Approach 2:
The patent adopts small molecule compounds with molecular weights typically below 500 Da, which are more stable and easier to produce than peptide compounds. These small molecules serve as stable, long-lasting inhibitors that do not require complex protection against enzymatic degradation, simplifying production and storage.
2Reliability
If peptide compounds with diproline mimetics are used, then binding affinity to VASP-EVH1 domain is improved, but stability against proteases deteriorates
Solution Approach 1:
The patent replaces unstable peptide bonds with stable non-peptidic chemical bonds, creating small molecule inhibitors that are resistant to proteolytic degradation. This structural transformation maintains the essential binding functionality while eliminating the vulnerability to enzymatic breakdown that plagues peptide-based inhibitors.
Solution Approach 2:
The patent creates hybrid molecular structures that combine the binding functionality of diproline mimetics with stable non-peptidic linkers and functional groups. This composite approach integrates the advantages of both peptide-based recognition and small molecule stability, resulting in inhibitors that maintain high affinity while achieving protease resistance.
3Reliability
If some polyproline mimetics are used, then protein-protein interaction inhibition is achieved, but cell permeability deteriorates
Solution Approach 1:
The patent optimizes molecular parameters including reducing molecular weight below 500 Da, adjusting lipophilicity through strategic placement of hydrophobic and hydrophilic groups, and minimizing hydrogen bond donors. These parameter optimizations enable the inhibitors to pass through cell membranes via passive diffusion while maintaining their ability to bind to target proteins and inhibit interactions.
Data Source
AI summary
The present invention relates to chemical compounds which can be used in particular as structural mimetics of proline-rich peptides. The compounds of the present invention are capable of selectively inhibiting Ena/VASP-EVH1-mediated protein-protein interactions. The invention further relates to the use of these compounds as pharmaceutical agents and the use of the pharmaceutical agents for the treatment of tumor diseases.