Synthesis of Membrane Permeable Macrocyclic Peptides Via Imidazopyridinium Grafting

Abstract: Macrocyclic peptides (MPs) are a class of compounds that have been shown to be particu-larly well suited for engaging difficult protein targets. However, their utility is limited by their generally poor cell permeability and bioavailability. Here we report an efficient solid-phase synthesis of novel MPs by trapping a reversible intramolecular imine linkage with a 2-formyl- or 2-keto-pyridine to create an im-idazopyridinium (IP+)-linked ring. This chemistry is useful for the creation of macrocycles of different sizes and geometries, including head-to-side and side-to-side chain configurations. Many of the IP+-linked MPs exhibit far better passive membrane permeability than expected for “beyond Rule of 5” mol-ecules, in some cases exceeding that of much lower molecular weight, traditional drug molecules. We demonstrate that this chemistry is suitable for the creation of libraries of IP+-linked MPs and show that these libraries can be mined for protein ligands.