title: Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline.
abstract: Chronic immune activation is a hallmark of progressive HIV infection. Recent reports point to the engagement of toll-like receptor 7 (TLR7) and -9 by viral RNA as contributing to the activation of innate immune responses, which drive viral replication leading to immune exhaustion. The only known class of TLR7 antagonists is single-stranded phosphorothioate oligonucleotides, which has been demonstrated to inhibit immune activation in human and Rhesus macaque in vitro models. The availability of a selective and potent small-molecule TLR7 antagonist should allow the evaluation of potential benefits of suppression of TLR7-mediated immune activation in HIV/AIDS. Gardiquimod is a known N(1)-substituted 1H-imidazoquinoline TLR7 agonist, the synthesis of which has not been published. We show that the 3H regioisomer is completely inactive as a TLR7 agonist and is weakly antagonistic. A des-amino precursor of the 3H regioisomer is more potent as a TLR7 antagonist, with an IC(50) value of 7.5 microM. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Lawrence, KS 66047, United States.
authors.forename: Nikunj M
authors.initials: NM
authors.lastname: Shukla
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kimbrell
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D007093:Imidazoles; D011804:Quinolines; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7