Rational design of small-molecule ligands based on structural information remains a significant challenge in chemical biology. In particular, given huge sizes of protein surfaces, little success has been gained in targeting protein-protein interfaces. The toll-like receptor (TLR) family proteins recognize microbial pathogens and trigger inflammatory and antiviral responses, thus play a key role in innate and adaptive immune responses. However, the immune response is a double-edged sword. Excessive activation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases. Nevertheless, there are still few small-molecule antagonists available. Our group have recently reported the first TLR8-specific small-molecule antagonists CU-CPT8m. (Zhang, S. et al. Nat. Chem. Biol. 2018, 14, 58-64) Furthermore, the X-ray crystal structure of TLR8 in complex with CU-CPT8m (Figure 1A) indicated that CU- CPT8m did not fully utilize the binding pocket. Herein, by structure-based rational design, we have discovered three exceptionally potent quinolones derivatives with pico-molar IC50 values. (Hu, Z. et al. Cell Chem. Biol. 2018, 25, 1286-1291) Three X-ray crystallographic structures validated the contacts within the binding pocket (Figure 1B-1D). These potent and selective small-molecule antagonists successfully target an unconventional pocket on a protein-protein interface. A variety of biological evaluations in cultured cell lines, primary cells, splenocytes from human TLR8-transgenic mice and specimen of rheumatoid arthritis patients further demonstrated the high efficacy of these TLR8 inhibitors, suggesting excellent therapeutic potential against autoimmune disorders. In conclusion, our designs showed the successful application of molecular recognition in drug development against conventionally undruggable targets.

Discovery of novel TLR8 antagonists via structure-based rational design

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.