Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the intestinal tract including Crohn's disease and ulcerative colitis. Current IBD treatments involve anti-inflammatory drugs, immunosuppressants, biologic agents and antibiotics, as well as drugs for symptomatic relief. IBD pathogenesis involves a complex interaction of host genetics, gut microbiota, innate immunity, and environmental factors. PepTl is a protoncoupled oligopeptide transporter of the SLC15 family, primarily found in the small intestine, kidney, and pancreas. PepTl is nutritionally important because it absorbs di- and tri-peptides from the diet. PepTl is also pharmacologically significant because it transports therapeutic agents such as beta-lactam antibiotics and antiviral nucleoside prodrugs in the intestines. Recent studies indicate that PepTl plays a key role in the intestinal inflammation of IBD by transporting bacterial-derived products into the cytosol to induce the NF-kappaB and MAPK signaling pathways, resulting in the synthesis of proinflammatory cytokines. PepTl is, therefore, a novel and important 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 a different target site within the enterocyte.Our goal is to identify small molecule modulators of PepTl transport (inhibitors or substrates) using ntegrated computational and experimental approaches and to examine their effect in relevant IBD mouse models. Specifically, we will take a structure-based discovery approach. We will first construct structural models of PepTl using homology modeling and Molecular Dynamics simulations. Second, we will virtually screen various purchasable small molecule libraries, including endogenous metabolites, prescription drugs, and lead-like compounds against PepTl models in various conformations. Our computations will then be followed by experimental testing of newly identified ligands using cell culture assays. Finally, we will rationally refine PepTl transport modulators and establish the importance of PepTl and its top hits in IBD using in situ and in vivo models in transgenic mice.This work will provide novel leads for designing specific small molecule drugs against a recently identified BD drug target. Moreover, because PepTl plays a key role in intestinal absorption, disposition, and dynamics of a wide range of peptides and peptide-like drugs, small molecule modulators identified in this study can be used to rationally design drugs with optimal oral bioavailability against many other diseases, including diabetes and cancer. Finally, PepTl belongs to the Major Facilitator Superfamily (MFS), one of most common strutural families of membrane transporters in nature. Describing the transport mechanism by PepTl will, therefore, contribute to our understanding of solute transport across membranes for other important MFS proteins, such as the human glucose transporters (GLUTs), which play a key role in diabetes and cancer.
|Effective start/end date||15/09/15 → 14/03/17|
- Congressionally Directed Medical Research Programs: $285,574.00