Macrocyclic Peptide Displays High Affinity for Key Protein

Researchers report that an iterative selection technique allowed them to identify a macrocyclic peptide with extraordinarily high affinity for a key signaling protein, suggesting that the technique, in their words, "provides a general route to design novel, low-molecular-weight, high-affinity ligands that target protein surfaces," (ACS Chem. Biol. 2007, 2, 625). Richard W. Roberts of the University of Southern California and coworkers carried out the study using mRNA display, an in vitro evolution method for identifying peptides that recognize specific targets. They generated about 1 trillion macrocyclic peptides containing a nonnatural amino acid and screened the molecules for binding to Gαi1, a signaling protein with potential relevance to several diseases. The selected macrocyclic peptide binds Gαi1 with 2-nM affinity—one of the strongest binding interactions ever described for peptides that recognize protein surfaces, Roberts says. Macrocyclic peptides containing nonnatural amino acids tend to be more stable and are predicted to enter cells more easily than linear peptides, making them promising drug candidates.