Brysa Alvarado, Graduate Student, Meisel Lab, GW Department of Chemistry

The Department of Chemistry Presents:  Brysa Alvarado, Graduate Student, Meisel Lab, GW Department of Chemistry.  

Targeting deep hydrophobic pockets in disease-associated proteins with small molecules remains a cornerstone of modern drug discovery. However, a substantial portion of the human proteome remains “undruggable”, as many proteins lack well-defined pockets and instead participate in protein–protein interactions (PPIs) that involve large, relatively flat binding surfaces. These extended surfaces are poorly suited for conventional small molecules, motivating the development of molecular scaffolds capable of mimicking protein structure and surface topography, commonly known as peptidomimetics. Arylamide foldamers are short, sequence-defined oligomers that adopt well-defined conformations in solution and can be synthesized to display side chains in spatial arrangements that emulate protein surfaces. As such, they represent promising scaffolds for disrupting PPIs. Despite this potential, the rational design of functionalized scaffolds requires precise control over conformational preferences in solution. A fundamental challenge, therefore, is to identify structural elements that govern backbone torsions and side chain presentation. We hypothesized that conformational bias in arylamide oligomers could be systematically tuned through substitution patterns around the arylamide bond linking adjacent monomers. To test this hypothesis, we designed and synthesized a series of arylamide foldamers with varied aromatic substitution patterns and functional group placements. Using single crystal X-ray diffraction in combination with one-dimensional and variable-temperature NMR spectroscopy, we examined the conformational preferences in both solution and solid state. These studies reveal that intramolecular hydrogen bonding and dipolar repulsions serve as primary determinants of conformation, and that strategic aryl substitution patterns enable predictable backbone conformations. Collectively, this work establishes design principles for conformational control of arylamide foldamers for the design of scaffolds for targeting protein surfaces. As for application and ongoing work, the arylamide scaffolds are being applied toward allosteric inhibition of a model protein PTPN1.

BIO

Brysa graduated from California State University San Marcos in 2020 with a B.S. in Biochemistry. While at CSUSM, she worked as an undergraduate researcher with Dr. Robert Iafe studying substitution reactions catalyzed by gold(I), strengthening her foundation in synthetic chemistry. In the summer of 2020, she moved to Washington, DC, to begin her Ph.D. in the Chemistry Department at GW, joining Dr. Joseph Meisel’s lab. Her graduate research focuses on organic synthesis and the conformational design of peptidomimetic and foldamer scaffolds to interact with protein targets.