UC Irvine

The agonists of Toll-like receptors (TLRs) are interesting targets for vaccine adjuvants and other immunotherapies. One particular challenge in their use is their poor pharmacokinetic properties. Targeted covalent inhibitors have been shown to have irreversible binding with the receptors of interest, leading to high selectivity and potency. These properties are very attractive for TLR agonists. In addition, it is currently not known what effect continuous activation of TLRs will have on immune activation. Drawing inspiration from ligand-directed tosyl chemistry, we have synthesized several potential covalent agonists of TLR 7/8 and evaluated them in biological assays. Additionally, we have made progress in determining if these agonists do indeed proceed through covalent modification of the receptor.