CU-CPT-9a is a Specific TLR8 Antagonist

The innate immune system senses the presence of pathogen associated molecular patterns (PAMPs) through a wide variety of germ-line encoded host sensors. They are pattern recognition receptors (PRRs). Toll-like receptor (TLR) family proteins play a crucial role in the initiation of the hosts’ immune responses. They link innate immunity and adaptive immunity. Upon PAMPs recognition, TLRs recruit a series of adaptor proteins. They trigger the proinflammatory signaling cascades that result in the activation of NF-κB, and upregulation of inflammatory cytokines and chemokines. In addition, this TLR response is crucial in helping eliminate the pathogen and establishing long lasting adaptive responses, but also can cause various autoimmune diseases and inflammatory disorders. Besides, humans have ten different TLRs. TLR7 and TLR8 are phylogenetically and structurally related, sharing little difference in sequence and structure homology. However, CU-CPT-9a is a specific TLR8 antagonist (IC50=0.5 nM).

CU-CPT9a can reverse the elevation of the downstream protein levels induced by R848 in a dose-dependent manner. Moreover, CU-CPT9a binds to TLR8 at a different site from small-molecule agonist. It significantly suppresses the TNF-α level in a dose-dependent manner. Furthermore, it is in agreement with previous reports of TLR8 involvement in these autoimmune diseases.

All in all, TLRs are homologous PAMP and danger-associated molecular pattern sensors in the innate immune system. In this study, the authors develop a high-throughput screening assay. It has an in-house engineered HEK-Blue 293 cell lines that stably overexpress human TLR8. CU-CPT9a can be as a chemical probe to understand biological relevance of TLR8 in different pathogenesis processes. Thus, CU-CPT9a presents significant therapeutic development potential.


Zhang S, et al. Nat Chem Biol. 2018 Jan;14(1):58-64.