Backbone Modification

G-protein-coupled receptors, GPCRs, mediate diverse physiological processes and are targets of many therapeutic agents. GPCR subfamilies comprise related receptors that can be activated by the same or similar agonists but manifest distinct functions.

Subtype-selective agonists are valuable as tools for fundamental research and as drug candidates with minimal side effects. It is challenging, however, to develop agonists with differentiated activities at structurally related receptors.

Researchers in the Gellman Lab, published in PNAS, started from a human parathyroid hormone fragment that is used to treat osteoporosis, and developed subtype-selective variants by modifying the peptide backbone while maintaining the natural side chains. Their findings suggest that backbone modification, which has received little prior attention in terms of tailoring polypeptide hormone specificity, may represent a general source of receptor-selective agonists.

Receptor Selectivity from Minimal Backbone Modification of a Polypeptide Agonist
Shi Liu, Ross W. Cheloha, Tomoyuki Watanabe, Thomas J. Gardella, and Samuel H. Gellman
PNAS December 4, 2018 115 (49) 12383-12388