ChemInform Abstract: Regioisomerism-Dependent TLR7 Agonism and Antagonism in an Imidazoquinoline

Autor: Nikunj M. Shukla, Matthew R. Kimbrell, Sunil A. David, Subbalakshmi S. Malladi
Rok vydání: 2009
Předmět:
Zdroj: ChemInform. 40
ISSN: 1522-2667
0931-7597
DOI: 10.1002/chin.200936153
Popis: 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.
Databáze: OpenAIRE
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