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Toll-like receptor 7 selective synthetic oligoribonucleotide agonists: synthesis and structure-activity relationship studies.

Abstract：

:We previously reported a novel class of stabilized immune-modulatory RNA (SIMRA) compounds that activates TLR8 or both TLR7 and TLR8 depending on the nucleotide composition and chemical modifications incorporated. In the present study, to identify TLR7-selective agonists, we designed and synthesized novel SIMRA compounds with varying sequence compositions substituting 7-deaza-G for natural guanosine and studied immune-stimulatory activity in cell-based assays and in vivo in mice. SIMRA compounds activated NF-kappaB in HEK293 cells expressing TLR7 and induced cytokine production in mouse spleen cells and human PBMCs and higher levels of IFN-alpha in human pDCs, which correlated with TLR7 activation. Subcutaneous administration of SIMRA compounds to mice increased serum cytokine levels. TLR knockout mouse studies showed that both TLR7 and MyD88 are required for activity of SIMRA compounds. The presence of a 5'-AA/CN (A > C and N = U/C/7-deaza-G) and/or C/AUU-3' (C > A) trinucleotide at the 5'- and 3'-ends of SIMRA compound along with a 5'-AN(1)N(2)UG1A-3' (N(1) = A/C; N(2) = U/C/7-deaza-G) or UG1AZ(1)G1Z(2)UU (Z(1) = A < C; Z(2) = C < A) motif confers TLR7 selectivity over other sequence compositions. In conclusion, we have designed and synthesized novel SIMRA compounds that selectively act as agonists of TLR7.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lan T,Dai M,Wang D,Zhu FG,Kandimalla ER,Agrawal S

doi

10.1021/jm901145s

subject

Has Abstract

pub_date

2009-11-12 00:00:00

pages

6871-9

issue

21

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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