Evaluation of Binding and Cell Penetration of Imidazolium Amino Acids as Novel Bioisosteres for Trimethyllysine, Dimethylarginine, and Arginine

Abstract Inhibition of histone trimethyllysine (Kme3) reader proteins is a promising therapeutic strategy due to their roles in gene regulation and disease, particularly cancer. However, developing effective inhibitors has proven challenging because of the extended, solvent-exposed binding interface and the cooperative reliance on interactions with multiple positively charged residues in the histone tail in addition to Kme3. While these cationic groups are often necessary for strong affinity binding, they reduce cell penetration of peptidic inhibitors, increasing the challenge of inhibitor development for this class of proteins. Herein we report the evaluation of three new imidazolium amino acids (IAAs) as novel lipophilic cationic bioisosteres for Kme3, dimethylarginine (Rme2), and Arg against a panel of histone reader proteins. We find that these biomimetics can replace Kme3, Rme2, and Arg, with similar or even improved binding in some cases, while also providing unique selectivity patterns relative to the parent amino acid. Moreover, we find that these imidazolium amino acids promote improved cytosolic penetration due to their increased lipophilicity and lack of hydrogen bond donors. These new lipophilic cationic amino acids provide promising new chemotypes for inhibition of histone reader proteins, as well as other protein–protein interactions that rely on cationic residues.