STRUCTURE-BASED DISCOVERY OF CD4-MHC CLASS II INHIBITORS

DESCRIPTION (provided by applicant): Our company aims to develop specific inhibitors of activated autoreactive CD4+ T cells implicated in multiple sclerosis (MS). Previously, our company's founding scientists successfully developed a novel CD4 peptide inhibitor for the clinical trial in humans. Now in this proposal, we propose to develop an entirely new class of non-peptidic, organic compounds as the second generation of inhibitors for MS, which will be highly potent, enzymatically stable, orally available, and cost-effective. In recent studies, our company's founding scientists used computer screening method to discover a small organic molecule, TJU103, to specifically inhibit activated CD4+ T cells (IC50 of ~10 uM) by disrupting the oligomerization and stabilization of the CD4- major histocompatibility complex class II interaction. The biological effect of TJU103 in vivo on acute experimental allergic encephalomyelitis (EAE), an animal model for the human MS was examined. When administered shortly before or after the onset of clinical symptoms, TJU103 reduced the severity of disease in the SJL and SWXJ-14 mouse models of EAE. Long-term inhibitory activity of a single injection of TJU103 was also demonstrated upon EAE rechallenge. In addition to the effect on the clinical symptoms of disease, a decrease in the pathological symptoms of disease was shown with TJU103. Secondary T cell responses to proteolipid protein (139-151) and keyhole limpet hemocyanin demonstrated that TJU103 also specifically affected the activated CD4+ T cells. The frequency of antigen-stimulated TH1 and TH2 cytokine-secreting cells was also shown to be reduced after in vivo TJU103 treatment. These results demonstrate the potential of the TJU103 organic inhibitor or modified analogs for future clinical application in MS and other CD4+ T cell mediated diseases. Thus, the goal of this proposal will be to expand upon these exciting findings to optimize the chemical and pharmacological properties of TJU103 and determine the efficacy and mechanism of TJU103-related analogs so that they will eventually be suitable for clinical studies in humans.