Macrocyclic peptides are promising molecules for targeting intracellular protein–protein interactions and other challenging biological targets. However, their poor membrane permeability often limits their biological and therapeutic applications. Understanding the structural factors that govern passive membrane permeation is therefore essential for the rational design of cell-permeable macrocyclic peptides.
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\r\nIn this seminar, I will present our recent efforts to understand and predict the membrane permeability of macrocyclic peptides using large-scale experimental data, conformational analysis, and machine learning. We aim to clarify how conformational flexibility, including molecular chameleonicity, influences membrane permeability.
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\r\nI will also introduce our ongoing efforts toward DNA-encoded macrocyclic N-methyl peptide libraries as a future platform for discovering functional intracellular binders.