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Bio:
Tahnee Dening is a Principal Scientist in the Discovery Pharmaceutics group within the Synthetic Molecule Pharmaceutical Sciences Department at Genentech in South San Francisco. She received her PhD from the University of South Australia and completed postdoctoral training at the University of Kansas, prior to joining Genentech. Her research focuses on the development and application of enabling formulations for challenging molecules and novel modalities, such as peptides, as well as characterizing and understanding peptide behavior in the gastrointestinal environment.

Summary:
The effect of peptide solution behavior (e.g. self-association tendency) on oral absorption potential when dosed with (and without) permeation enhancers, such as sodium decanoate, has not been comprehensively studied. In this work, we dosed two peptides intrajejunally to rats with and without sodium decanoate. These two peptides are close structural analogs, sharing over 80% sequence homology. One peptide had significantly higher bioavailability than the other when dosed with (and without) sodium decanoate. We utilized molecular dynamics simulations and biophysical experiments (e.g. fluorescence spectroscopy, dynamic light scattering, proton nuclear magnetic resonance spectroscopy) to assess the differences in solution behavior between the two peptides. The less bioavailable peptide was observed to self-associate in solution to form pentamers, which we hypothesized had a negative effect on its absorption both with and without sodium decanoate as a permeation enhancer. To address this, we designed mutated analogs of the less bioavailable peptide to alter its solution behavior, and characterized the solution behavior of these mutants in silico and in vitro.