Soluble ligands as drug targets for treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is characterized by persistent inflammation in a hereditarily susceptible host. In addition to gastrointestinal symptoms, patients with IBD frequently suffer from extra-intestinal complications such as fibrosis, stenosis or cancer. Mounting evidence supports the targeting of cytokines for effective treatment of IBD. Cytokines can be included in a newly proposed classification “soluble ligands” that has become the third major target of human protein therapeutic drugs after enzymes and receptors. Soluble ligands have potential significance for research and development of anti-IBD drugs. Compared with traditional drug targets for IBD treatment, such as receptors, at least three factors contribute to the increasing importance of soluble ligands as drug targets. Firstly, cytokines are the main soluble ligands and targeting of them has demonstrated efficacy in patients with IBD. Secondly, soluble ligands are more accessible than receptors, which are embedded in the cell membrane and have complex tertiary membrane structures. Lastly, certain potential target proteins that are present in membrane-bound forms can become soluble following cleavage, providing further opportunities for intervention in the treatment of IBD. In this review, 49 drugs targeting 25 distinct ligands have been evaluated, including consideration of the characteristics of the ligands and drugs in respect of IBD treatment. In addition to approved drugs targeting soluble ligands, we have also assessed drugs that are in preclinical research and drugs inhibiting ligand-receptor binding. Some new types of targetable soluble ligands/proteins, such as epoxide hydrolase and p-selectin glycoprotein ligand-1, are also introduced. Targeting soluble ligands not only opens a new field of anti-IBD drug development, but the circulating soluble ligands also provide diagnostic insights for early prediction of treatment response. In conclusion, soluble ligands serve as the third-largest protein target class in medicine, with much potential for the drugs targeting them.