Developing Novel PepT1-Targeted Modulators for Inflammatory Bowel Disease (IBD) Therapy
Abstract
The two major forms of inflammatory bowel disease (IBD), Crohn s disease and ulcerative colitis, are chronic disorders characterized by nonspecific inflammation and intestinal tissue damage. IBD incidence and prevalence have been increasing with time and in different regions around the world, indicating its emergence as a global disease, particularly of the Western Society and Northern America. Current IBD treatments involve anti-inflammatory drugs, immunosuppressants, biologic agents and antibiotics, as well as drugs for symptomatic relief. PepTl is a protein that is primarily found in the small intestine where it absorbs dietary degradation products and therapeutic agents such as antibiotics and antiviral drugs. Recent studies suggest that PepTl is also present in the colon of IBD patients and plays a key role in inflammation by transporting bacterial-derived products into the intestinal cells. PepTl is, therefore, an important and novel IBD drug target, in which PepTl inhibitors can be used to block the uptake of harmful peptides of bacterial origin or PepTl substrates to efficiently deliver anti-inflammatory agents to problematic intestinal cells. Our goal is to discover new chemical tools to modulate and explore PepTl function, using a structure-based discovery approach and transgenic mice models, with a long-term objective of developing innovative medicines for IBD. In structure-based virtual screening, a large library of small molecules is computationally screened against the structure of a biological target. This is a fast and cheap method, which is based on the protein structure rather than the structure of known chemicals, and has been demonstrated to be a powerful tool in identifying new chemical entities that are distinct from the known chemicals normally associated with the target. For a protein target without an experimentally determined structure, such as PepTl, virtual screening can be performed against structural models that are based on experimentally determined structures of related proteins. In the past few years, several crystal structures of non-human PepTl have been determined, providing excellent templates for characterizing the structure and dynamics of the human PepTl. This structural information, coupled with the progress in computer-aided drug design methodologies and computational power, as well as with the development of relevant animal models, has expanded the applicability of rational structure-based drug-design to target human PepTl for the treatment of IBD. Our proposed project is interdisciplinary, employing methods from computational chemistry, cell biology, molecular pharmacology, and model organism genetics. Our proposal involves the following three key hypotheses: (1) Structural modeling will allow us to understand the specificity determinants of PepTl inhibition and activation; it will provide a framework to generate additional hypotheses about PepTl mechanism that will be tested with functional approaches. (2) Small molecule modulators of PepTl can be predicted accurately with virtual screening against PepTl models, and newly identified modulators will have observable effects in cell-based assays. (3) Our novel transgenic mice capture PepTl substrate specificity and pharmacokinetic/dynamic properties, including absorption, systemic exposure, and tissue distribution, which are needed for IBD drug discovery. In summary, PepTl is an emerging drug target for the treatment of IBD. The expected results of this project will provide novel chemical tools to further characterize PepTl s pathophysiological function and a framework for developing distinct and potent drugs for treating IBD. Moreover, because PepTl facilitates the intestinal uptake of a wide range of prescription drugs, new chemical entities identified in this study can be used to rationally design drugs with optimal oral bioavailability against many other diseases, including diabetes and cancer. Finally, Pe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510539
Entities
People
- Avner Schlessinger
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army