Beyond cyclosporine A: Charting Islands of Bioavailability Beyond the Rule of 5?
Scott Lokey
CSO, Circle Pharma
There has been a renewed interest in bioactive cyclic peptides and peptidomimetics, and new synthesis and screening technologies have enabled the discovery of potent macrocycles against a wide variety of biological targets. Many cyclic peptides found in nature show suprisingly good cell permeability and even oral bioavailability, and yet producing synthetic cyclic peptides with drug-like pharmacokinetic properties has not seen widespread success. Cyclic peptide natural products often share common backbone features, such as N-methylation, that we hypothesize serve to enhance lipophilicity and proteolytic stability, but our understanding of the interplay between these structural elements and their contribution to the physicochemical properties of cyclic peptides remains murky. I will present my groups efforts over the past several years to decipher structure-property relationships in cyclic peptide natural products, toward developing a set of guidelines for the synthesis of non-natural cyclic peptides with favorable pharmacokinetic properties, including oral bioavailability.
Scott Lokey received his Bachelors of Science in Chemistry from Trinity University in San Antonio, Texas in 1989, and then went on to receive his PhD in Chemistry from UT Austin in 1997 under the mentorship of Dr. Brent Iverson. He then received an NIH postdoctoral fellowship to do research on cyclic peptides at the Harvard Institute of Chemistry and Cell Biology in Boston, Massachusetts, where he worked on the identification of cyclic peptide modulators of actin dynamics under the guidance of Timothy Mitchison. Dr. Lokey was appointed to the position of Assistant Professor of Chemistry at the University of California Santa Cruz in 2002, where he has continued to pursue the basic science underlying cell permeability in cyclic peptides. He has developed methodologies for synthesizing backbone-modified cyclic peptides, and through a collaboration with Prof. Matthew Jacobson at UCSF, he has applied computational approaches for predicting membrane permeability in non-Lipinski Rule-of-5 molecules, especially cyclic peptides. Dr. Lokey and Dr. Jacobson are co-founders of Circle Pharma, a biotech startup whose mission is to enable the discovery of membrane-permeable cyclic peptides against intracellular targets of high therapeutic value.