Small molecule therapeutics have the advantage of oral administration, increased tissue penetration, and ease of production. The discovery and development of small molecules can be challenging due to the absence of known ligand chemotypes and the need for extensive structural optimization. To overcome these challenges a rational drug design approach utilizing multiple strategies like high throughput screening, and structure-based fragment identification can be implemented. In these projects, we have investigated the therapeutic targets for autoimmune disorders.

Project 1: Type 1 diabetes mellitus (T1DM) is characterized by the autoimmune destruction of insulin-secreting β cells by autoreactive T cells, leading to loss of cellular uptake of glucose. T1DM is strongly linked to genetic susceptibility from the locus encoding the major histocompatibility complex (MHC) class II, specifically the haplotype of HLA-DQ8. To inhibit the activation of autoreactive T cells, here we have utilized a structure-guided ligand design approach by targeting the interaction between T1DM susceptible HLA-DQ8 and Insulin peptide B (9:23).

Project 2: Cytokines are key mediators of inflammation and are prominently involved in autoimmune and inflammatory diseases and play key roles in the pathogenesis of diseases such as rheumatoid arthritis, osteoarthritis, and systemic lupus erythematosus. We propose to profile a panel of 34 human cytokines to identify small-molecule ligands and inhibitors. We recently validated and published a platform approach that successfully identified the first lead small-molecule inhibitor for the cytokine IL-4, and here we expand this approach to the larger suite of disease-relevant cytokines.

For Interleukin-4 (IL-4), we have taken the lead small-molecule inhibitor forward and synthesized its homologs which are currently undergoing structure-activity relationships for enhancing its affinity and potency for IL-4 inhibition.

Daniel Sheehy

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