Abnormal production of tumor necrosis factor-alpha (TNF ) has been implicated in autoimmune disorders including Crohn's disease which causes inflammation of the gastrointestinal tract. Current therapies of Crohn's disease have limited efficacy and more efficient, drug-like therapeutics are currently being sought after8. The binding event of TNF with its 55 kDa receptor (TNF-R55) is part of a signal cascade that leads to inflammation. The crystal structure of a closely related cytokine, TNF bound to the extracellular, soluble domain of TNF-R55 (sTNF-R55) has previously been used to create a homology model of the interaction between TNF and sTNF-R55. This model was used by Greene et al. to design a constrained peptide mimetic of TNF-R55 that disrupts this interaction9. Proposed here is the design and synthesis of small molecule mimetics of TNF-R55 hypothesized to be potential inhibitors of the interaction between TNF and sTNF-R55. The initial inhibitor design utilizes a guanine scaffold.
The first aim of this project is the synthesis of two small libraries of compounds, an alanine scan of constrained peptides based on the sequence of the TNF-R55 domain being mimicked and a tri-functionalized guanine library.
The second aim i s the structure activity relationship study of these libraries using in vitro and in silico methods.
The third aim i s the synthesis of a second library of compounds based on the results of aims one and two.
Crohn's disease is a debilitating autoimmune disorder that affects the gastrointestinal tract. Current therapies require injection and have poor efficacy with many side effects. This research proposes to use small, orally available therapeutics that have been designed using the mechanism of current therapies for Crohn's disease.
|Davis, Jessica M; Colangelo, Julie (2013) Small-molecule inhibitors of the interaction between TNF and TNFR. Future Med Chem 5:69-79|