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Literature DB >> 21355588

Small-molecule inhibitors of the TLR3/dsRNA complex.

Abstract

The protein-RNA interface has been regarded as "undruggable" despite its importance in many biological processes. The toll-like receptor 3 (TLR3)/double-stranded RNA (dsRNA) complex provides an exciting target for a number of infectious diseases and cancers. We describe the development of a series of small-molecule probes that were shown to be competitive inhibitors of dsRNA binding to TLR3 with high affinity and specificity. In a multitude of assays, compound 4a was profiled as a potent antagonist to TLR3 signaling and also repressed the expression of downstream signaling pathways mediated by the TLR3/dsRNA complex, including TNF-α and IL-1β.

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Year: 2011 PMID： 21355588 PMCID： PMC3068529 DOI： 10.1021/ja111312h

Source DB: PubMed Journal: J Am Chem Soc ISSN： 0002-7863 Impact factor: 15.419

20 in total

1. Simultaneously monitoring DNA binding and helicase-catalyzed DNA unwinding by fluorescence polarization.

Authors: H Q Xu; A H Zhang; C Auclair; X G Xi
Journal: Nucleic Acids Res Date: 2003-07-15 Impact factor: 16.971

Review 2. Solution-phase combinatorial libraries: modulating cellular signaling by targeting protein-protein or protein-DNA interactions.

Authors: Dale L Boger; Joel Desharnais; Kevin Capps
Journal: Angew Chem Int Ed Engl Date: 2003-09-15 Impact factor: 15.336

3. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.

Authors: Thomas A Halgren; Robert B Murphy; Richard A Friesner; Hege S Beard; Leah L Frye; W Thomas Pollard; Jay L Banks
Journal: J Med Chem Date: 2004-03-25 Impact factor: 7.446

4. Toll-like receptor signaling pathways.

Authors: Gregory M Barton; Ruslan Medzhitov
Journal: Science Date: 2003-06-06 Impact factor: 47.728

5. Application of a novel in silico high-throughput screen to identify selective inhibitors for protein-protein interactions.

Authors: Catherine Joce; Joshua A Stahl; Mitesh Shridhar; Mark R Hutchinson; Linda R Watkins; Peter O Fedichev; Hang Yin
Journal: Bioorg Med Chem Lett Date: 2010-07-30 Impact factor: 2.823

6. Selection, Preparation, and Evaluation of Small- Molecule Inhibitors of Toll-Like Receptor 4.

Authors: Douglas E Bevan; Alexander J Martinko; Lisa C Loram; Joshua A Stahl; Frederick R Taylor; Sampada Joshee; Linda R Watkins; Hang Yin
Journal: ACS Med Chem Lett Date: 2010-04-12 Impact factor: 4.345

7. TLR3 increases disease morbidity and mortality from vaccinia infection.

Authors: Martha Hutchens; Kathryn E Luker; Peter Sottile; Joanne Sonstein; Nicholas W Lukacs; Gabriel Núñez; Jeffrey L Curtis; Gary D Luker
Journal: J Immunol Date: 2008-01-01 Impact factor: 5.422

8. Structural basis of toll-like receptor 3 signaling with double-stranded RNA.

Authors: Lin Liu; Istvan Botos; Yan Wang; Joshua N Leonard; Joseph Shiloach; David M Segal; David R Davies
Journal: Science Date: 2008-04-18 Impact factor: 47.728

9. Double-stranded RNA-induced inducible nitric-oxide synthase expression and interleukin-1 release by murine macrophages requires NF-kappaB activation.

Authors: M R Heitmeier; A L Scarim; J A Corbett
Journal: J Biol Chem Date: 1998-06-12 Impact factor: 5.157

10. Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors.

Authors: Shuting Zhang; Kui Cheng; Xiaohui Wang; Hang Yin
Journal: Bioorg Med Chem Date: 2012-08-25 Impact factor: 3.641

Small-molecule inhibitors of the TLR3/dsRNA complex.

1. Simultaneously monitoring DNA binding and helicase-catalyzed DNA unwinding by fluorescence polarization.

Review 2. Solution-phase combinatorial libraries: modulating cellular signaling by targeting protein-protein or protein-DNA interactions.

3. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.

4. Toll-like receptor signaling pathways.

5. Application of a novel in silico high-throughput screen to identify selective inhibitors for protein-protein interactions.

6. Selection, Preparation, and Evaluation of Small- Molecule Inhibitors of Toll-Like Receptor 4.

7. TLR3 increases disease morbidity and mortality from vaccinia infection.

8. Structural basis of toll-like receptor 3 signaling with double-stranded RNA.

9. Double-stranded RNA-induced inducible nitric-oxide synthase expression and interleukin-1 release by murine macrophages requires NF-kappaB activation.

10. Toll-like receptor 3 signaling on macrophages is required for survival following coxsackievirus B4 infection.

1. IL-22 suppresses HSV-2 replication in human cervical epithelial cells.

2. Activation of TLR3/interferon signaling pathway by bluetongue virus results in HIV inhibition in macrophages.

3. The development of antimicrobial a-AApeptides that suppress proinflammatory immune responses.

Review 4. Toll-like receptors and chronic inflammation in rheumatic diseases: new developments.

Review 5. Therapeutic Developments Targeting Toll-like Receptor-4-Mediated Neuroinflammation.

6. Cardiomyocyte Maturation Requires TLR3 Activated Nuclear Factor Kappa B.

7. Toll-like receptor (TLR)-7 and -8 modulatory activities of dimeric imidazoquinolines.

8. Human Cervical Epithelial Cells Release Antiviral Factors and Inhibit HIV Replication in Macrophages.

9. Discovery of small-molecule inhibitors of the TLR1/TLR2 complex.

10. Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors.