Structure-based rational design of TLR7/8 antagonists through agonist scaffold reengineering for psoriasis therapy.

Toll-like receptors 7 and 8 (TLR7/8) play pivotal roles in modulating the body's immune response, and their antagonists provide promising treatment options for autoimmune diseases. Here, by modifying the structure of TLR7 agonist SMU-L11, we developed a series of TLR7/8-specific antagonists with therapeutic potential for psoriasis. Experimental validation revealed that structural restriction of the N1 substituent was critical for the pharmacological efficacy of the inverted parent scaffold. Among derivatives, SMU-R39 was the optimal compound, demonstrating potent TLR7/8 inhibitory activity. In vitro studies confirmed that SMU-R39 directly binds to TLR7/8 and effectively suppresses downstream NF-κB and MAPK signaling pathways, thereby significantly reducing the secretion and transcription of pro-inflammatory cytokines in immune cells. Furthermore, in vivo studies demonstrated that SMU-R39 can markedly alleviate murine psoriasis-like skin inflammation and ameliorate histopathological tissue damage, while concurrently downregulating the transcription levels of key cytokines. Our study provides novel small-molecule antagonist specifically targeting TLR7/8 and establishes TLR7/8 antagonist as a viable therapeutic strategy for treating autoimmune diseases.