Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline

Nikunj M. Shukla, Matthew R. Kimbrell, Subbalakshmi S. Malladi, Sunil A. David

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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 N1-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 IC50 value of 7.5 μM. This class of compound may serve as a starting point for the development of small-molecule inhibitors of TLR7.

Original languageEnglish (US)
Pages (from-to)2211-2214
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number8
StatePublished - Apr 15 2009
Externally publishedYes


  • Agonist
  • Antagonist
  • Innate Immunity
  • TLR7
  • Toll-like receptors


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