Regioisomerism-dependent TLR7 agonism and antagonism in an imidazoquinoline.
Bioorg Med Chem Lett
; 19(8): 2211-4, 2009 Apr 15.
Article
em En
| MEDLINE
| ID: mdl-19285861
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Quinolinas
/
Receptor 7 Toll-Like
/
Imidazóis
Limite:
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article