Imidazolium Amino Acids Proposed as Bioisosteres for Methylated Lysine and Arginine Residues
- Imidazolium amino acids are proposed as cationic bioisosteres mimicking the size and charge of trimethyllysine, dimethylarginine, and arginine side chains.
- Binding to methyl-lysine reader domains is evaluated to see how closely the surrogates reproduce native residue recognition and selectivity.
- Cell assays indicate the charged isosteres can still traverse membranes, and SAR trends tie ring substitution to the affinity-permeability tradeoff for reader ligands and CPPs.
💡 Points
A non-hydrolyzable Kme3/Rme2 mimic solves a genuine headache—native methylated peptides get erased by demethylases or clipped by proteases mid-assay, muddying SAR. If ring substitution tunes affinity without killing permeability, this is a genuine alternative scaffold for reader-domain PPI inhibitors and arginine-free CPPs, not just another quaternary-ammonium curiosity—worth testing against our own Kme3 reader panel.