Peptide macrocycles: From structural studies to oral bioavailability

Peptides represent a therapeutic modality that has received renewed interest over the past several years. While this surge of activity can be partially explained by the emergence of new technologies for targeted delivery of peptide drugs, there are also reasons to be optimistic about structure-based improvement of key properties of peptides that have traditionally been viewed as liabilities. Large polar surface area is one of these properties. Macrocyclic topology allows one to minimize polar surface area of peptides by increasing the propensity to form intramolecular hydrogen bonds while shielding them from solvation.

We have developed several enabling methods that allow for rapid synthesis of peptide macrocycles and their evaluation as potential therapeutic agents. I will present not only the foundational aspects of this technology, but also the progress we have made in the area of inflammatory bowel disease, wherein our lead molecule recently showed positive efficacy data in a 12-day colitis study. We attribute this and other successes to our emerging understanding of the structure/activity relationship in macrocycles. I will also present our new data in the area of boron-containing peptides. This new class of molecules holds promise for the development of tool compounds to interrogate complex protease targets.