Plecanatide is a synthetic, 14-amino acid peptide analog of the endogenous human hormone uroguanylin. It is designed to mimic the structure and function of uroguanylin, which is a key regulator of fluid and electrolyte transport in the gastrointestinal epithelium. The peptide was discovered and developed as a targeted therapy for functional gastrointestinal disorders, specifically chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Its significance lies in its novel mechanism of action as a guanylate cyclase-C (GC-C) receptor agonist, which promotes natural secretory processes in the gut, offering a physiological approach to managing constipation with a favorable safety profile due to its localized action within the intestinal lumen.
Quick Facts
| Also Known As | SP-304, MD-1100 |
|---|---|
| Sequence | Nle-Cys-Glu-Leu-Cys-Val-Asn-Val-Ala-Cys-Thr-Gly-Cys-Leu |
| Molecular Formula | C65H104N18O26S4 |
| Molecular Weight | 1681.9 Da |
| PubChem CID | 70693500 |
Research Parameters
| Half-Life | Unknown (as an orally administered peptide designed for local luminal action, systemic pharmacokinetics are minimal and not the primary determinant of its effect) |
|---|---|
| Stability | As a formulated oral tablet, stability data are proprietary. For the pure peptide in a research context, typical lyophilized peptide stability applies: stable for years at -20°C when protected from light and moisture. Stability after reconstitution in aqueous buffers would be limited (likely hours to days at 2-8°C) due to susceptibility to degradation. |
| Solubility | For research purposes, the pure peptide powder may be soluble in sterile water or slightly acidic buffers. However, its clinical formulation is a solid oral tablet designed for delayed release. |
| Storage (Lyophilized) | -20°C or below, protected from light and moisture, in a desiccated environment. |
| Storage (Reconstituted) | If reconstituted for experimental use, store at 2-8°C and use immediately or within a short timeframe (e.g., 24 hours) due to stability concerns. |
| Typical Research Dose | In clinical research, the effective oral dose is 3000 mcg (3 mg) daily. Preclinical research doses vary based on model and route. |
| Cycle Parameters | In clinical research protocols for CIC and IBS-C, administration is a continuous daily oral dose (e.g., 3 mg/day) over study periods typically lasting 12 weeks, with some long-term extension studies up to 52 weeks. |
| Amino Acid Count | 14 |
Mechanism of Action
Plecanatide exerts its primary effects by selectively binding to and activating the guanylate cyclase-C (GC-C) receptor on the luminal surface of intestinal epithelial cells. This activation triggers a well-defined intracellular signaling cascade that results in increased fluid secretion and accelerated intestinal transit.
GC-C Receptor Activation: Upon binding, plecanatide activates the GC-C receptor, stimulating the intracellular production of cyclic guanosine monophosphate (cGMP).
Increased Intracellular cGMP: The elevated intracellular cGMP acts as a second messenger, activating protein kinase G (PKG) and protein kinase A (PKA) pathways.
CFTR Channel Phosphorylation: Activated PKG and PKA phosphorylate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, increasing its open probability and facilitating chloride and bicarbonate secretion into the intestinal lumen.
Fluid Secretion and Transit: The secretion of ions creates an osmotic gradient that draws water into the intestinal lumen, softening stool and stimulating peristalsis. This mechanism is pH-sensitive, mimicking uroguanylin's enhanced activity in the more acidic environment of the proximal small intestine, which may contribute to its physiological regulation of transit.
Research Applications
Chronic Idiopathic Constipation (CIC): Research demonstrates plecanatide significantly increases the frequency of spontaneous bowel movements (SBMs) and improves stool consistency in patients with CIC. Clinical trials have shown it to be effective and well-tolerated, leading to its FDA approval for this indication.
Irritable Bowel Syndrome with Constipation (IBS-C): In IBS-C, plecanatide research has focused on its ability to alleviate multiple symptoms, including abdominal pain, bloating, and straining, while normalizing bowel function. It is approved for the treatment of IBS-C in adults.
Gastrointestinal Motility Disorders: Preclinical and clinical research investigates its potential role in other disorders characterized by slowed transit or secretory dysfunction, exploring its utility as a physiological modulator of intestinal fluid homeostasis.
Safety & Side Effects
The most common side effects reported in clinical trials are gastrointestinal in nature, including diarrhea, abdominal distension, flatulence, and abdominal pain. Diarrhea was the most frequently reported adverse event and was typically mild to moderate in severity. Serious adverse events were rare. There are theoretical concerns regarding electrolyte imbalance (e.g., hyponatremia, hypokalemia) with severe diarrhea, but this was not commonly observed in controlled trials. No anecdotally reported side effects beyond those documented in clinical studies are widely recognized.
Dosage Information
For research and educational purposes only. This information is derived from published human clinical trials. In approved clinical use for CIC and IBS-C, the typical dose is 3 mg taken orally once daily. The peptide is administered as an oral tablet designed to remain intact until it reaches the gastrointestinal tract. The frequency is daily, and the duration of use in studies has ranged from 12-week pivotal trials to longer-term (up to 52-week) safety studies.
References
Shailubhai, K., et al. 'Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses.' Digestive Diseases and Sciences, 2013.
Barish, C.F., et al. 'Efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 trials.' American Journal of Gastroenterology, 2017.
DeMicco, M., et al. 'Efficacy and safety of plecanatide in patients with chronic idiopathic constipation: results of two phase 3 trials.' American Journal of Gastroenterology, 2017.
Fogel, R., et al. 'Efficacy and safety of plecanatide for the treatment of chronic idiopathic constipation: results from two phase 3 trials.' Therapeutic Advances in Gastroenterology, 2018.
Palmer, M., et al. 'Plecanatide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation.' Drugs of Today, 2018.
Brenner, D.M., et al. 'Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials.' American Journal of Gastroenterology, 2018.