Discovery of new small molecule TLR4 agonists for the treatment of allergic rhinitis

The long term goal of this proposal is the development of an intranasal stand alone TLRagonist to treat allergic rhinitisUnlike antigen specific therapythis allergen independent approach will be broadly applicable to a vast array of allergens patients are exposed toSuch treatment would provide relief within hours of administrationproviding short term symptom controland has the potential to deliver long term disease remission via allergen dependent T cell and B cell memory responsesThe first objective of this proposal is to identify new small molecule TLRagonists via high throughput virtual screening of a large library of commercially available compounds using known TLRMDcrystal structuresThe second objective is to confirm human and murine TLRactivity of the hits using HEKTLRcell lines and evaluate a selected set of hTLRagonists for cytokine inductioncytotoxicity and ILinhibition in PBMCAfter lead optimization in Objectivetwo leads will be evaluated in Objectivefor their ability to modulate Thallergic response in an established mouse model of acute allergic pulmonary inflammationThe innovation of this proposal lies in using high throughput virtual screening to identify new small molecule TLRagonistsand the use of nonLPS likeTLRagonists for the treatment of allergy