Pharmacology
Systemic absorption of the globular tetradecapeptide is minimal.Linaclotide, like the endogenous guanylin and uroguanylin it mimics, is an agonist that activates the cell surface receptor of guanylate cyclase 2C (GC-C). The medication binds to the surface of the intestinal epithelial cells. Linaclotide is minimally absorbed and it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C increases cyclic guanosine monophosphate (cGMP). Elevated cGMP stimulates secretion of chloride and bicarbonate and water into the intestinal lumen, mainly by way of cystic fibrosis transmembrane conductance regulator (CFTR) ion channel activation. This results in increased intestinal fluid and accelerated transit. By elevating cGMP, linaclotide is also considered to reduce activation of colonic sensory neurons, reducing pain; and activates colonic motor neurons, which increases smooth muscle contraction and thus promotes bowel movements. Chemistry
Linaclotide is a hybrid peptide design of the E.coli heat-stable enterotoxin (STa) and the endogenous peptide hormones endogenous guanylin and uroguanylin.
It is a synthetic tetradecapeptide (14 amino acid peptide) with the sequence CCEYCCNPACTGCY by one-letter abbreviation, or by three-letter abbreviation:H–Cys1–Cys2–Glu3–Tyr4–Cys5–Cys6–Asn7–Pro8–Ala9–Cys10–Thr11–Gly12–Cys13–Tyr14–OH
However, the actual structure of linaclotide is not fully specified without the three disulfide (R-S-S-R) bonds it contains, which are between Cys1 and Cys6, between Cys2 and Cys10, and between Cys5 and Cys13; these are shown in exaggerated fashion in the line-angle graphic showing the chemical bonds within and between each amino acid (and their stereochemistries, see the infobox, above right), and are represented using a one-letter abbreviations in the following additional schematic:

A study in discovery synthesis reported that 2 of 14 strategies available to synthesize linaclotide were successful—the successful ones involving trityl protection of all cysteines, or trityl protection of all cysteines except Cys1 and Cys6, which were protected with tert-butylsulphenyl groups. The study also reported that solution-phase oxidation (disulfide formation) was advisable over solid-supported synthesis for linaclotide, and that the Cys1–Cys6 disulfide bridge was the most favored energetically. History
The drug was discovered at Microbia, Inc, which had been spun out of the Whitehead Institute in 1998 by postdocs from the lab of Gerald Fink to commercialize the labs know-how and inventions related to microbial pathogens and biology. In 2002 the company hired Mark Currie who had worked at the Searle division of Monsanto and then had gone to Sepracor. Currie directed the efforts that led to the discovery of linaclotide, which was based on an enterotoxin produced by some strains of Escherichia coli that cause travelers diarrhea.