| Description |
The immune system is the body's defense against pathogens. Since it has to be able to withstand the fast-evolving nature of microscopic invaders, the immune system has a variety of mechanisms to recognize and destroy them. One way that pathogens are recognized is through toll-like receptor (TLR) signaling that is present on innate immune cells. These receptors can either distinguish intracellular or extracellular components and signal an immune response. However, occasionally these receptors are activated even in the absence of a disease-causing agent leading to autoimmune disorders. This can prompt issues such as Lupus and other autoimmune issues. The focus of this research is to design a PROTAC, Proteolysis Targeting Chimeras, that can couple an E3-ligase inhibitor to a TLR inhibitor to degrade specific toll-like receptors. To test the effectiveness of these PROTAC systems, variants of a pyrazole fragment which contain a dibrominated chain that can be attached to the E3-ligase inhibitor thalidomide are synthesized to modify the connector chain to optimize its length and functionality to see how it affects inhibitory activity. Luciferase and Alimar Blue assays will be performed and if these different PROTACs are shown to safely decrease the TLR activity could lead to the production of medical therapies that could be used to treat the overactivation of the immune system in instances where it is not beneficial. |
