Pharmacology and clinical potential of guanylyl cyclase C agonists in the treatment of ulcerative colitis

Figures & data

Figure 1 The guanylyl cyclase C agonists.

Notes: Known primary amino acid structures of the agonists of guanylyl cyclase C. Residues shown in green on the structures on the right indicate amino acid substitutions in synthetic ligands compared with respective biological homologs. The amino acid sequence for ST reflects that of the heat-stable enterotoxin isoform STh produced by Escherichia coli.

Figure 2 Physiological functions regulated by endogenous GCC agonists in the intestine.

Notes: The diagram indicates the principal putative biological responses elicited by endogenous hormones guanylin and uroguanylin upon binding and activation of GCC on intestinal brush-border membranes.
Abbreviation: GCC, guanylyl cyclase C.

Figure 3 GCC and its downstream targets. (A) The domain structure of GCC. (B) Key proximal effectors activated by GCC in intestinal epithelial cells upon catalytic conversion of GTP to cGMP.

Abbreviations: cAMP, cyclic adenosine monophosphate; CaR, calcium-sensing receptor; CFTR, cystic fibrosis transmembrane conductance regulator; cGMP, cyclic guanosine monophosphate; CNG, cyclic nucleotide gated channel; GCC, guanylyl cyclase C; GTP, guanosine-5′-triphosphate; PDE, phosphodiesterases; PKA, protein kinase A; PKG, protein kinase G; VASP, vasodilator-stimulated phosphoprotein.

Figure 4 GCC agonists as ulcerative colitis therapeutics.

Notes: In ulcerative colitis, abnormal immune responses and colonic inflammation reflect inappropriate luminal antigen exposure for disruption of the mucosal barrier integrity (left panel). Pathogenetic mechanisms underlying loss of intestinal barrier function, in turn, include mutually reinforcing processes of cell lineage imbalance, defective mucus layer, tight junction disassembly and epithelial cell hyper-permeability (left panel). Administration of GCC agonists reconstitutes normal environment-immune interactions by restoring the colonic mucosal barrier integrity, in part, through the promotion of cell lineage-dependent homeostasis, optimal superficial mucus layer and epithelial cells’ tight junctions (right panel).

Abbreviation: GCC, guanylyl cyclase C.