Developing Novel PepT1-Targeted Modulators for Inflammatory Bowel Disease (IBD) Therapy
Technical Report,15 Sep 2015,14 Sep 2016
Icahn School of Medicine at Mount Sinai New York United States
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The overarching research goal of this project is to contribute to the understanding of inflammatory bowel disease IBD mechanisms by providing an integrated experimental and computational description of substrate specificity in the human Proton-coupled oligopeptide transporter, PepT1 SLC15A1. The methodologies include structure-based drug discovery computations, combined with cell-based and in vivo models of IBD. During the past year, we have made significant progress toward completing our Project Goals. We have continued to characterize structure-function relationships in PepT1. IN particular, we i developed structural models for PepT1 in different conformations, ii predicted small molecule ligands using virtual screening, and iii tested the model and ligands experimentally using the yeast P. pastori, to refine the initial models and optimize ligands. These results confirm the relevance of the PepT1 model for drug discovery as well as reveal previously unknown chemical scaffolds that interact with this transporter. Furthermore, our results provide a framework for developing more potent ligands in various cellular and animal IBD models, directly addressing Aims 2 and 3 of our Project Goals.
- Medicine and Medical Research