Peptoid PRMT Inhibitors Using Protease-Resistant Backbones
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Solution Overview
Problem
Existing peptide-based inhibitors of protein arginine methyltransferases (PRMTs) are susceptible to proteolysis, limiting their in vivo utility as therapeutic agents due to rapid degradation, and current chemical probes and small molecule inhibitors often cause off-target effects.
Innovation Solution
Development of peptoid-based inhibitors that mimic the N-terminal tail of histone H4, which are more stable and selectively inhibit PRMT1 and PRMT5 by attaching the amino acid side chain to the nitrogen in the amide backbone, reducing length and incorporating a positive charge at the N-terminus for enhanced binding.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If peptide-based inhibitors are used to target PRMTs, then selectivity among enzymes is improved, but stability against proteolysis deteriorates leading to rapid degradation
Solution Approach 1:
The patent creates peptoid copies that mimic the structure and function of natural peptide substrates. These peptoid inhibitors replicate the key structural features needed for PRMT binding while using a protease-resistant backbone structure, thus achieving both selectivity and stability
Solution Approach 2:
The patent modifies the fundamental chemical parameters of the peptide backbone by shifting the side chain attachment from the α-carbon to the nitrogen atom. This parameter change fundamentally alters the molecule's resistance to proteolysis while preserving its ability to bind PRMT enzymes selectively
2Reliability
If small molecule inhibitors are used to target PRMTs, then in vivo utility is improved, but off-target effects increase
Solution Approach 1:
The patent concentrates the interaction specificity at the local binding interface between the peptoid and PRMT active site. By designing the peptoid side chains to match the specific amino acid sequence recognized by each PRMT isozyme, the invention achieves high local complementarity that ensures selective binding without broad off-target effects
Data Source
AI summary
Novel peptoid compounds, compositions and methods of using the compounds and compositions to inhibit protein arginine methyltransferase (PRMT) and induce apoptosis in cancer cells are presented.