Christopher Grubb, Graduate Student, Meisel Lab, GW Department of Chemistry

Many therapeutically interesting protein-protein interactions (PPIs) occur along large, flat, solvent-exposed protein surfaces. Due to the nature of these interaction surfaces, PPIs are difficult to target with small molecule ligands. Macrocyclic peptides and peptidomimetics are characterized by broader surfaces with precisely displayed functional groups and are therefore well-suited to inhibit PPIs. Macrocycles are typically more flexible than small molecule ligands and overcoming conformational heterogeneity remains a challenge in their design. As such, there is a need to develop generalizable methods to control macrocycle conformation in solution. In this work, we investigate how stereosequence—the sequence of chiral monomers in an oligomer—affects the conformation of peptidomimetic macrocycles. We synthesized a library of oligomers using solid phase peptide synthesis methods and cyclized them to form peptidomimetic macrocycles. Using variable temperature and two-dimensional nuclear magnetic resonance combined with circular dichroism spectroscopy techniques, we studied conformational changes that arise from the stereosequence of endocyclic alpha amino acids. We found specific intramolecular hydrogen bonds are critical in transmitting stereochemical information throughout the peptide backbone. This information is conveyed through the secondary structure of linear and macrocyclic oligomers and highlights the role that stereosequence plays in controlling conformation of our macrocycles.

Bio

Chris graduated from the University of Montana in Missoula, MT in 2017 with a B.S. in Chemistry. While at UM, Chris worked as an undergraduate researcher with Dr. Orion Berryman working to develop thiourea-based organocatalysts. In 2020, Chris started a PhD at The George Washington University where he joined Dr. Joe Meisel’s group shortly after. Since then, he has been studying conformational control of peptidomimetic macrocycles.

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