GC-C Agonists - Basic Science and Mechanism-of-Action

SP-304 – A Drug to Treat Gastrointestinal Disorders

SP-304 is a new member of a novel class of non-systemic drugs for treatment of chronic constipation (CC), constipation-predominant irritable bowel syndrome (IBS-C) and other GI diseases.  SP-304 is a synthetic analog of a natural peptide hormone called uroguanylin that regulates ion and fluid transport in the GI tract.
 
Uroguanylin and the Guanylate Cyclase C Receptor

Uroguanylin, a peptide hormone predominantly secreted in the GI tract, was discovered in the early 1990’s (1, 2). It is secreted predominantly in the intestinal tract where it functions by binding to a unique receptor found on epithelial cells of the intestine. This receptor, called guanylate cyclase C (GC-C), mediates synthesis of intracellular cyclic GMP (cGMP), a key regulator of cellular function. One key biochemical response mediated by uroguanylin is the activation of a chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR), leading to augmented flow of chloride and water into the lumen of the gut to facilitate bowel movement.

Certain bacteria, including E. coli, produce an enterotoxin called ST-peptide that is structurally related to uroguanylin. This peptide can over-activate the GC-C receptor, promoting unregulated fluid transport into the intestine, and producing what is commonly called travelers’ diarrhea.

The Development of SP-304

Uroguanylin is a linear peptide comprised of 16 amino acids in length that is folded into a three-dimensional structure (or conformation) containing two intra-molecular disulfide linkages. This spatial structure and rigidity gives the hormone considerable stability in the intestinal tract.  Although uroguanylin is temperature and protease resistant, it exists in both active and inactive conformers in aqueous solution, complicating its development as a drug.

Starting in 2000, Synergy scientists, using structure-function studies, developed a series of analogs of uroguanylin, leading to the identification of SP-304. A single key amino-acid substitution enabled the Synergy team to create a drug, SP-304, with superior pharmacological properties (3). Unlike uroguanylin, SP-304 exists primarily in a single bioactive conformation. Orally administered SP-304 binds to and activates guanylate cyclase C (GC-C) expressed on the epithelial cells lining the GI mucosa, resulting in activation of CFTR, and leading to an augmented flow of chloride and water into the lumen of the gut to facilitate bowel movement. In animal models, oral administration of SP-304 promotes intestinal secretion and ameliorates gastrointestinal inflammation. 

GC-C agonists for treatment of Chronic Constipation and IBS-C

Water plays a vital physiological role in the intestine. Proper water content of the intestinal lumen ensures normal transport of the content through the bowel. Water also facilitates maintenance of the intestinal mucus layer, which protects the GI mucosa from mechanical damage and the harmful effects of stomach acid and bacterial or viral pathogens. Too low water content can cause constipation, whereas too high water content, as occurs in diseases like cholera and in incidents of food poisoning (eg. E. coli GI infections), typically leads to diarrhea. One of the major functions of uroguanylin is to regulate fluid and ion transport into the lumen of the intestine.

In the GI tract, uroguanylin is produced by goblet cells and excreted into the lumen of the intestine. Uroguanylin then diffuses within the intestine to GC-C receptors on epithelial cells.

Uroguanylin Function as Fluid Regulator in Intestine

Upon activation, the GC-C receptor promotes intracellular synthesis of cGMP, leading to activation of CFTR and secretion of chloride and bicarbonate into the intestinal lumen. Water is also transported with the salt ions. The end result is a looser intestinal content more easily transported through the bowel.

Agonists of GC-C receptor thus provide a novel approach to the treatment of CC and IBS-C. Recent clinical data reported on a similar drug have validated the use of GC-C receptor agonists to treat CC and IBS- C (4, 5).

References

1. Hamra FK, Fan X, Krause WJ, Freeman RH, Chin DT, Smith CE, Currie MG, Forte LR. Prouroguanylin and proguanylin: purification from colon, structure, and modulation of bioactivity by proteases. Endocrinology. 1996 Jan;137(1):257-65.
2. Forte, L.R., Guanylin regulatory peptides: structures, biological activities mediated by cyclic GMP and pathobiology. Reg. Pept., 81:25-39, 1999.
3. Shailubhai, K., G. Nikiforavich and Jacob, G.S. Guanylate Cyclase receptor agonists for the treatment of tissue inflammation and carcinogenesis. U.S. Patent 7,041,786, Issue may 9, 2006.
4. Viola Andresen, Michael Camilleri, et al., Effect of 5 Days Linaclotide on Transit and Bowel Function in Females With Constipation-Predominant Irritable Bowel Syndrome.. Gastroenterology 2007;133:761–768
5. Currie MG, Kurtz CB, Mahajan-Miklos S, et al. Effects of a single dose administration of MD-1100 on safety, tolerability, exposure, and stool consistency in healthy subjects. Am J Gastoenterol. 2005;100:S328.
6. Refaat AF. Hegazi, Fengling Li, Gabriel Calilao, Antonia Sepulveda, Kunwar Shailubhai, Scott E. Plevy SP304, an analog of uroguanylin, ameliorates inflammation in a model of experimental colitis. Abstract, presented at Digestive Disease Week, 2005
7. Shailubhai. K. Therapeutic applications of guanylate cyclase receptor agonists. Curr. Opin. Drug Disc. Dev. 5(2): 2002.