7rc9
Crystal structure of human TLR8 ectodomain bound to small molecule antagonist 21Crystal structure of human TLR8 ectodomain bound to small molecule antagonist 21
Structural highlights
FunctionTLR8_HUMAN Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.[1] Publication Abstract from PubMedThe toll-like receptors (TLRs) play key roles in activation of the innate immune system. Aberrant activation of TLR7 and TLR8 pathways can occur in the context of autoimmune disorders due to the elevated presence and recognition of self-RNA as activating ligands. Control of this unintended activation via inhibition of TLR7/8 signaling holds promise for the treatment of diseases such as psoriasis, arthritis, and lupus. Optimization of a 2-pyridinylindole series of compounds led to the identification of potent dual inhibitors of TLR7 and TLR8, which demonstrated good selectivity against TLR9 and other family members. The in vitro characterization and in vivo evaluation in rodent pharmacokinetic/pharmacodynamic and efficacy studies of BMS-905 is detailed, along with structural information obtained through X-ray cocrystallographic studies. Identification of 2-Pyridinylindole-Based Dual Antagonists of Toll-like Receptors 7 and 8 (TLR7/8).,Sreekantha RK, Mussari CP, Dodd DS, Pasunoori L, Hegde S, Posy SL, Critton D, Ruepp S, Subramanian M, Salter-Cid LM, Tagore DM, Sarodaya S, Dudhgaonkar S, Poss MA, Schieven GL, Carter PH, Macor JE, Dyckman AJ ACS Med Chem Lett. 2022 Apr 25;13(5):812-818. doi: , 10.1021/acsmedchemlett.2c00049. eCollection 2022 May 12. PMID:35586440[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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