Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline

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.