Gastroenterology

Gastroenterology

Volume 148, Issue 3, March 2015, Pages 483-487
Gastroenterology

Commentary
Guanylate Cyclase C Agonists: Emerging Gastrointestinal Therapies and Actions

https://doi.org/10.1053/j.gastro.2015.01.003Get rights and content

Section snippets

Chemistry of GC-C Receptor Agonists

UG, guanylin (GN), lymphoguanylin, and bacterial enterotoxin ST of E coli (which is responsible for travelers’ diarrhea) are structurally related peptides that activate the GC-C receptor, which is selectively expressed in brush border membranes of enterocytes from the duodenum to the rectum.4 Complementary DNAs encoding the precursors of GN, UG, and lymphoguanylin have been isolated, revealing that the active peptides are found at C-terminal ends of 100–116 amino acid proteins that possess

Intestinal and Colonic Chloride Secretion

Linaclotide is the first GC-C agonist approved for moderate to severe IBS-C and chronic idiopathic constipation.11, 12, 13 Pharmacodynamic studies showed that the GC-C agonist accelerated gastrointestinal transit,14 probably through increased fluid secretion. Preclinical studies (discussed elsewhere in this article) showed that it reduced visceral hypersensitivity. Linaclotide acts locally in the gastrointestinal tract with minimal systemic exposure, resulting in low oral bioavailability and,

Future Directions

GC-C agonists have demonstrated clinical impact as laxatives and visceral analgesics. Future research is likely to elaborate on anti-inflammatory and antineoplastic effects of this pathway, its mediators, and its modulators. These increasingly understood actions may, in fact, have an even greater impact in clinical practice than the actions on secretion and visceral sensation. The advances, from understanding a pathogenic toxin to a new drug class with many potential therapeutic benefits,

References (35)

  • T. Fiskerstrand et al.

    Familial diarrhea syndrome caused by an activating GUCY2C mutation

    N Engl J Med

    (2012)
  • M. Camilleri et al.

    RNA sequencing shows transcriptomic changes in rectosigmoid mucosa in patients with irritable bowel syndrome-diarrhea: a pilot case-control study

    Am J Physiol

    (2014)
  • N.S. Joo et al.

    Regulation of intestinal Cl- and HCO3-secretion by uroguanylin

    Am J Physiol

    (1998)
  • L.R. Forte et al.

    Guanylin: A peptide regulator of epithelial transport

    FASEB J

    (1995)
  • F.K. Hamra et al.

    Regulation of intestinal uroguanylin/guanylin receptor-mediated responses by mucosal acidity

    Proc Natl Adad Sci U S A

    (1997)
  • K. Shailubhai et al.

    Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses

    Dig Dis Sci

    (2013)
  • S. Rao et al.

    A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation

    Am J Gastroenterol

    (2012)
  • Cited by (34)

    • Just how prevalent are peptide therapeutic products? A critical review

      2020, International Journal of Pharmaceutics
      Citation Excerpt :

      Linaclotide and plecanatide are both agonists of guanylate cyclase-C (GC-C), and they have local effects on the luminal surface of the intestinal epithelium. The activation of GC-C ultimately leads to accelerated GI transit and increased release of intestinal fluid (Camilleri, 2015). Elobixibat is minimally absorbed in circulation when taken orally; however, it acts locally in the lumen of the GI tract by binding to and partially inhibiting ileal bile acid transporter (IBAT) in the ileal mucosa (Acosta and Camilleri, 2014).

    • Theoretical structural characterization of lymphoguanylin: A potential candidate for the development of drugs to treat gastrointestinal disorders

      2017, Journal of Theoretical Biology
      Citation Excerpt :

      Up to now, three drugs derived from GPs or guanylin-like peptides have been approved or are in the approval process at the US Food and Drug administration (FDA): Linaclotide (Ironwood Pharmaceuticals Inc, Boston, MA, USA and Forest Laboratories Inc, New York, NY, USA) is derived from E. coli STa, while Plecanatide and Dolcanatide (Synergy Pharmaceuticals Inc, New York, NY, USA) are both analogs of UGN used to treat gastrointestinal disorders, despite UGN renal function. These drugs have been described as excellent options for the treatment of gastrointestinal disorders such as irritable bowel syndrome with constipation (Busby et al., 2010; Camilleri, 2015; Shailubhai et al., 2013), chronic idiopathic constipation (Camilleri, 2015; Shailubhai et al., 2015) and ulcerative colitis (Shailubhai et al., 2015, 2013). For this reason, analogs of GPs could be considered as promising drugs for controlling gastrointestinal disorders.

    View all citing articles on Scopus

    Conflicts of interest The author declares no conflicts.

    View full text