Linaclotide and plecanatide are synthetic peptide agonists of guanylate cyclase-C (GC-C), a transmembrane receptor that is predominantly located on intestinal epithelial cells. These medications have very low oral bioavailability, which, when combined with the expression profile of GC-C, provides a mechanism of action ‘targeted to the gut’.
Linaclotide has been shown to inhibit colonic nociceptors and reduce peripheral drive from the colon, resulting in reduced numbers of activated dorsal horn neurons within the spinal cord and reduced pain responses to noxious colorectal distension. These effects are greatest in animal models of chronic visceral hypersensitivity that drive the ‘bottom-up’ and/or ‘top-down’ sensitization relevant to irritable bowel syndrome (IBS).
Activation of GC-C results in the generation and release of cyclic guanosine-3′,5′-monophosphate (cGMP) from intestinal epithelial cells. When released into the submucosal space through the basolateral membrane, extracellular cGMP acts as a neuromodulator to inhibit pain-sensing nerve fibers innervating the colon. cGMP has also been demonstrated to inhibit pain-sensing nerves from human donors.
In all human Phase III clinical studies conducted to date in patients with irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC), linaclotide significantly improved abdominal pain, discomfort, and bloating.
Recent preclinical studies also provide the prospect that linaclotide may offer a novel therapeutic option, not only for the treatment of chronic abdominal pain in IBS-C, but also comorbid bladder dysfunction and endometriosis-associated pain.
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3′,5′-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.
Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Current diagnosis of IBS is based on symptoms enshrined in the multiple iterations of Rome criteria and exclusion of pathophysiology based on standard clinical testing. Subclassifications of IBS are determined by the nature of stool irregularities, such as those experiencing constipation (IBS-C), diarrhea (IBS-D), or alternating constipation and diarrhea (IBS-M). Additionally, chronic idiopathic constipation (CIC) affects ~14% of the global population. Symptoms associated with CIC diagnosis include reduced bowel movements, hard stools, straining during defecation, as well as bloating and discomfort. Thus, CIC patients have some symptoms that overlap with those of IBS-C. Given the clinical burden of these conditions, efficacious therapies are necessary. There are multiple efficacious treatments for bowel dysfunction, as illustrated in systematic reviews and network meta-analyses in patients with chronic constipation or IBS-C. However, there is a major unmet need in the management of symptoms such as pain and bloating. Although there are many candidate approaches in development as visceral analgesics, one of the more attractive pharmacological approaches involves the peripherally acting guanylate cyclase-C (GC-C) agonists, linaclotide and plecanatide. These agonists ‘tap’ into the intrinsic mechanisms controlling intestinal fluid homeostasis, which are regulated by the endogenous hormones uroguanylin and guanylin. Importantly, linaclotide and plecanatide have limited bioavailability and hence have clinical safety as well as being bereft of central adverse effects, unlike traditional analgesics such as μ-opioids or centrally acting neuromodulators and most available cannabinoid agents.
Uroguanylin and guanylin are endogenous hormones of the guanylin peptide family of cGMP-regulating peptides, which regulate fluid secretion in response to meals, aiding in the digestive process. Uroguanylin is a 16-amino acid peptide expressed by tuft-like epithelial cells, which are primarily located within the proximal small intestine, with fewer cells in stomach, distal small intestine, and colorectum. Uroguanylin activates GC-C, which is abundantly expressed in intestinal epithelial cells, with greatest potency in the slightly acidic (pH 6) environments of the duodenum and proximal jejunum. In contrast, guanylin is a 15-amino acid peptide that is predominantly expressed in the colorectum by goblet cells. Guanylin activates GC-C in neutral to slightly basic pH environments. Upon binding by the natural hormones uroguanylin and guanylin, the intrinsic guanylate cyclase activity of GC-C rapidly elevates the intracellular concentration of the second messenger cGMP via the enzymatic conversion of cytoplasmic guanosine triphosphate (GTP) to cyclic GMP (cGMP). cGMP is involved in the regulation of a broad range of physiological processes, including the activation of cGMP-dependent protein kinase II (PKG-II) and a direct interaction with cyclic nucleotide-gated ion channels and cGMP-regulated phosphodiesterases. The role of cGMP in PKG-II phosphorylation and protein kinase A (PKA) activation is important for intestinal secretion, as they regulate the activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which is colocalized with PKG-II at the apical surface of intestinal epithelial cells. Increased activity of CFTR leads to the efflux of Cl¯ and HCO 3¯ ions into the intestinal lumen and promotes water secretion into the gastrointestinal tract. Furthermore, cGMP-activated PKG-II inhibits the activity of the sodium/hydrogen exchanger 3 protein (NHE3), blocking absorption of sodium ions from the intestinal lumen and inhibiting fluid absorption. The important role of GC-C in intestinal fluid homeostasis is confirmed in studies using GC-C gene knockout (gucy2c–/–) mice. Furthermore, in humans, gain of function mutations in GC-C are associated with chronic diarrhea, whilst loss of function mutations in GC-C have been associated with meconium ileus, which is characterized by neonatal intestinal obstruction. The mechanisms by which GC-C regulates intestinal secretion are reviewed in-depth elsewhere.
Linaclotide is a synthetic, selective 14-amino acid peptide agonist of GC-C, composed of naturally occurring amino acids, and that shares some sequence similarities with guanylin and uroguanylin. Linaclotide’s structure was designed with three disulfide bonds (Cys 1–Cys 6, Cys 2–Cys 10, Cys 5–Cys 13) to stabilize its molecular structure, enhance its resistance to degradation, and lock it into a constitutively active conformation.
