Anchoring epitopes to improve grafted peptide structure and activity (#220)
Peptides typically need to be constrained to overcome thermodynamic and metabolic limitations. However, design guidelines to obtain a successfully constrained peptide, and thus facilitate transition from loop to drug, are poorly formulated. In this poster, I will present work in which we survey the structures of interface loops and find the position of the terminal residues to be a key determinant of conformation. We use this knowledge to improve the process of molecular grafting, a valuable approach for constraining and stabilizing peptides by fusing them to a suitable scaffold. We show that an informed choice of where a loop is 'anchored' to a scaffold improves its form and function. We demonstrate that this knowledge can improve design outcomes using a range of epitopes and scaffolds. Overall, this study shows that an informed choice of loop and its matching scaffold can increase the success rate of designing stable and potent peptide drug leads.
- Yin, H.; Craik, D. J.; Wang, C. K. Angewandte Chemie International Edition 2019, 58, 7652-7656.