Protein-Protein Interactions

Q: Why peptides?
A: Peptides are highly active and selective effectors that can be routinely and inexpensively synthesized.

Q: Why cyclizations?
A: Cyclizations improve peptides' structural organization and therefore reduce the entropic penalty upon binding to a receptor. In addition, cyclizations help peptides resist proteolysis, even to the point of enabling oral bioavailability.

Q: What are macrocyclic peptides good for?
A: By offering larger binding interfaces than small molecules, peptides are capable of modulating "non-druggable" protein-protein interactions -e.g., they can provide a more affordable and effective alternative to therapeutic antibodies.

Q: Why non-natural amino acids?
A: They increase structural diversity, reduce immunogenicity, and make peptides more resistant to proteolysis.

Q: Why de novo design, rather than more routine library screening?
A: Screening-based approaches are inherently limited when used to pursue desirable non-proteinogenic amino acids, either due to the limitations of biology, or just because of the prohibitive combinatorial complexity. Moreover, de novo design is way less expensive than screening and provides much better coverage of the chemical space.