Cyclic PAR4 Peptides Inhibit Tumor Growth
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Solution Overview
Problem
Current peptide-based therapies for cancer, particularly aggressive types of breast cancer, face challenges due to poor drug-like properties, such as low stability and selectivity, limiting their clinical potential.
Innovation Solution
Development of peptides derived from the pleckstrin homology (PH)-domain binding motif of protease-activated receptor 4 (PAR4) and its analogs, specifically cyclic peptide analogs, which inhibit the interaction between PAR4 and Akt, offering enhanced stability and selectivity for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If peptides are used as therapeutic agents for cancer, then they can target specific receptors and signal transduction pathways, but they exhibit poor drug-like properties including low stability to enzymatic degradation and poor oral bioavailability
Solution Approach 1:
The patent applies parameter changes by modifying the peptide structure through cyclization (changing from linear to cyclic form) and incorporating non-natural amino acid residues. These structural parameter changes enhance stability to enzymatic degradation while preserving the ability to bind to PAR receptors and inhibit signal transduction pathways involved in cancer development.
2Reliability
If peptides are used as therapeutic agents, then they can provide targeted therapy, but they exhibit poor oral bioavailability
Solution Approach 1:
The patent modifies peptide parameters by cyclizing the peptide structure and incorporating non-natural amino acids, which improve membrane permeability and resistance to gastrointestinal degradation. These changes enhance oral bioavailability while maintaining the targeted therapy capability through specific binding to PAR receptors.
3Reliability
If PAR4 cytoplasmic tail peptides are used to inhibit PAR signal transduction, then they can treat cancer, but they may lack selectivity and affect other PAR receptors
Solution Approach 1:
The patent applies local quality by designing peptides with specific sequences derived from the PAR4 cytoplasmic tail that target particular binding interfaces. By optimizing local sequence features and incorporating specific amino acid residues, the peptides achieve selective inhibition of PAR4-mediated signal transduction while minimizing off-target effects on other PAR receptors.
Data Source
AI summary
The present invention provides peptides derived from the cytoplasmic region of protease-activated receptors 4 (PAR4) as well as analogs and cyclic analogs, such as backbone cyclic analogs, of these peptides. Pharmaceutical compositions comprising said peptides, analog, cyclic analogs and well as conjugates thereof are provided as well. The peptides, analogs and conjugates of the present invention and pharmaceutical composition comprising thereof have several uses including treating cancer such as cancer expressing PAR proteins such as cancer expressing ErbB protein and triple negative cancer. and inhibiting interactions between PARs and protein comprising PH-domain.