The Lubell laboratory applies the strength of organic synthesis to explore the chemical-biology of peptides through conformational restriction. Innovating methods for amino acid, polyamide and heterocycle synthesis, we study the medicinal chemistry of peptide structures by diversity-oriented approaches to create so called “peptidomimetic” prototypes for drug discovery. Our projects focus typically on unnatural peptides that possess novel mechanisms of action for modulating biological activity.
Peptide backbone geometry is defined by the φ (phi), ψ (psi) and ω (omega) dihedral angle values (Figure 1). Side chain orientations are defined by χ torsion angle values. Although local restrictions may combine with hydrophobic effects, van der Waals interactions, and hydrogen-bonds to overcome peptide solvation and give rise to relatively stable folded protein three-dimensional structures from longer peptides, shorter linear peptides (i.e., <10 residues) exist normally in dynamic equilibria of interconverting conformations. We explore the strategic use of stereoelectronic, covalent and steric constraints to restrict dihedral angles with consequences on global geometry that offset the dynamic equilibria, remove the entropy penalty for folding, and pre-organize conformations for receptor binding affinity.
Figure 1. Peptide dihedral angles
Group Picture 2019