Danielle Gomes Rodrigues, Graduate Student, Meisel Lab, GW Department of Chemistry

The Department of Chemistry Presents:  Danielle Gomes Rodrigues, Graduate Student, Meisel Lab, GW Department of Chemistry.  

Small-molecule ligands capable of recognizing protein surfaces offer a promising strategy to address the challenge of targeting proteins that lack well-defined binding pockets, collectively described as the ‘undruggable’ proteome. Despite the therapeutic value of targeting these proteins, conventional drug discovery methods have proven insufficient. Cyclic peptides have emerged as a promising scaffold well-suited for the broad, shallow, and polar surfaces of proteins. However, due to the flexibility of cyclic peptides, new strategies are needed for the conformational control required to match the ligand with the protein surface topography. To address this, we introduce stereosequence—the pattern of chiral centers in an oligomer backbone—as a key design element for structural tuning. Further, we introduce a synthetic δ-amino acid with an aromatic backbone, 2,4-MAMBA (2,4-dialkoxy-meta-aminomethylbenzoic acid), to modulate macrocycle rigidity. A library of six stereoisomeric macrocycles was created to evaluate these concepts as conformational determinants. Structural analysis using NMR and circular dichroism revealed that each stereoisomer adopts a distinct conformation. Functionalization of these macrocycles did not significantly impact their conformation. Notably, one stereoisomer exhibited trans-annular hydrogen bonds reminiscent of β-sheets with an intramolecular twist that, upon packing, induces a supramolecular helix, observed by X-ray crystallography. A second synthetic amino acid, 2,6-MAMBA, was designed to evaluate the importance of aryl substitution pattern on oligomer conformation. We found that the aryl substitution pattern affects hydrogen bonding and dipolar repulsion and therefore influences conformation, allowing for an additional design tool for peptide structural tuning. Our work establishes stereosequence as a powerful design parameter for conformational control in macrocyclic peptides and introduces new modular elements to enable the next generation of surface-targeting ligands.

BIO

Dani earned her B.A. in Biochemistry from Hamilton College in upstate New York in 2019. She joined the Chemistry Department at George Washington University in 2020 and is currently a member of Dr. Meisel’s lab. Her research focuses on controlling the conformation of cyclic peptides through the strategic incorporation of L- and D-amino acids. In her free time, she enjoys listening to true crime podcasts and spending time with her cat, Enid.