7r52 | pdb_00007r52
Crystal structure of human TLR8 in complex with Compound 2
Structural highlights
Function[TLR8_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 PubMedInappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8, starting from a co-crystal structure of a small screening hit. Further optimization of the physicochemical properties for cellular potency and expansion of the structure-activity relationship for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated in vivo efficacy after oral dosing. Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist.,Betschart C, Faller M, Zink F, Hemmig R, Blank J, Vangrevelinghe E, Bourrel M, Glatthar R, Behnke D, Barker K, Heizmann A, Angst D, Nimsgern P, Jacquier S, Junt T, Zipfel G, Ruzzante G, Loetscher P, Limonta S, Hawtin S, Andre CB, Boulay T, Feifel R, Knoepfel T ACS Med Chem Lett. 2022 Mar 10;13(4):658-664. doi:, 10.1021/acsmedchemlett.1c00696. eCollection 2022 Apr 14. PMID:35450354[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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