Plecanatide is an analog of the natural occurring uroguanylin peptide with a single amino acid substitution for higher receptor affinity which was approved in early 2017 by the FDA for the treatment of chronic idiopathic constipation (CIC). Similar to linaclotide, this peptide is administered in a daily oral dosage format (1). The mechanism of action takes place at the Gyanylate Cyclase C receptor found in the small intestines which upon binding of this peptide agonist triggers production of the cGMP. This messenger in turn activates protein kinases which phosphorylate the Cystic Fibrosis Trans Receptor (CFTR) to release Cl– and CO3-2 into the lumen of the intestine. As a result of a buildup of these anions, H2O also moves into the lumen by osmosis which softens the stool.
Plecanatide is a 16 residue peptide stabilized by two disulfide bonds which link Cys4 to Cys 12 and Cys7 to Cys15 (shown above, 2). Interestingly, the peptide has a pH and thermally sensitive switch built into the molecule (in the form of a topoisomer) that facilitates inactivation of the molecule which significantly lowers the undesired side effect of diarrhea.