College of Pharmacy
It is widely believed that imidazoquinolines stimulate the innate immune response by triggering Toll Like Receptors 7 and 8 (TLR 7/8) which, in turn, activate the NF-kappaB mediated production of pro-inflammatory cytokines and chemokines. These compounds have found widespread application in the design and development of vaccine adjuvants and for use as single agent treatments for skin diseases. This group has discovered an imidazoquinoline analog that is a potent activator of cytokine production, but does not trigger TLR 7/8. They have shown that TLR 7/8 activity can be regained by strategic chemical substitution to the imidazoquinoline structure. The work indicates that imidazoquinolines can function through an alternative mechanism of action that does not rely on TLRs, opening new avenues for the design and development of improved immunotherapies.
This project focuses on the design of novel TLR ligands using molecular modeling techniques. The x-ray crystal structure of the TLR-8 homdimer will be used as a template for building binding site models of newly synthesized imidazoquinoline analogs. A homology-based model of the TLR-7 homdimer will also be built based on the template. The structures will be applied to validate SAR data derived from biological assays and to guide the synthesis of new analogs.