Orally Delivered Peptides for Treatment of Inflammatory Bowel Disease

Challenges in the treatment of inflammatory bowel disease (IBD) include eliminating symptoms, enhancing safety, maintaining long-term remission, and ultimately discovering a cure. The treatment paradigm for IBD involves a range of drugs that escalate in convenience, cost, and side effects as patients lose response to prior treatment. Initial treatment uses the mildest form of antiinflammatory drug therapy, which is nontargeted and suppresses the entire human system; subsequent treatment employs targeted biologics that are injected and block immune pathways in healthy and diseased tissue; later stages of treatment may require surgery. The oral delivery of gastrointestinal (GI)-restricted agents directed at diseased GI tissue represents an ideal therapeutic management scenario. Such a strategy promises to maximize drug levels at relevant sites of action, leading to enhanced efficacy while minimizing systemically driven side effects. However, the GI tract provides a set of chemical, metabolic, and physical barriers that hinder the development of orally delivered therapeutic agents. Additionally, targeted therapies are typically biologics that modulate "undruggable" targets, and are challenging to deliver orally, necessitating the use of injectable agents. While such injectables have revolutionized IBD treatment, their utility is compromised by issues of systemic immunosuppression and intolerance. We propose the use of constrained peptides as oral targeted agents for IBD treatment. In this article, we summarize the chemical and biological stability characteristics of constrained peptides in the context of diseased GI physiology. Such peptides are candidates for therapeutics that are able to act from the luminal side (by oral delivery) to modulate clinically validated targets of current injectable biologics. This route is expected to yield high drug levels in diseased tissue while minimizing systemic availability and improving efficacy, safety, and durability.