<i>N</i>-Sulfonylanthranilic Acid Derivatives as Allosteric Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase

Yin, Zheng; Chen, Yen-Liang; Kondreddi, Ravinder Reddy; Chan, Wai Ling; Wang, Gang; Ng, Ru Hui; Lim, Joanne Y.H.; Lee, Wan Yen; Jeyaraj, Duraiswamy A.; Niyomrattanakit, Pornwaratt; Wen, Daying; Chao, Alex; Glickman, J. Fraser; Voshol, Hans; Mueller, Dieter; Spanka, Carsten; Dressler, S.; Nilar, Shahul; Vasudevan, Subhash G.; Shi, Pei Yong; Keller, Thomas H.

doi:10.1021/jm901044z

Cited by 58 publications

(47 citation statements)

References 21 publications

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“…Chemistry synthesis was performed to study the SAR of the "hit." The details of the SAR results were recently published (45). The SAR study generated NITD-2 which had an improved IC 50 of 0.7 M (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Docking and molecular simulation suggest that the compound binds to the RNA template formed between the fingers and thumb subdomains; the detailed methods for modeling was recently reported (45). Two RdRp residues, Arg737 and Thr413, form distinct hydrogen bond interactions with the inhibitor; the observed interactions were maintained during the course of the dynamics simulations, indicating their roles in stabilizing the compound in the allosteric binding pocket (45). Sequence alignment showed that residue Arg737 is conserved among mosquito-borne flavivirus NS5, whereas residue Thr413 is divergent among various members of flavivirus.…”

Section: Resultsmentioning

confidence: 99%

“…Compound synthesis and structure-activity relationship (SAR) studies were recently published (45). Compound NITD-1 was an initial "hit" identified from a DENV RdRp HTS.…”

Section: Methodsmentioning

confidence: 99%

“…NITD-29 contained a photoalkylating group benzophenone (2) and was synthesized for a UV cross-linking experiment to map the compound-binding site on the DENV NS5 protein. The synthesis of NITD-29 was described elsewhere (45).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Inhibition of Dengue Virus Polymerase by Blocking of the RNA Tunnel

Niyomrattanakit

Chen

Dong

et al. 2010

J Virol

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107

116

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Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. Neither vaccine nor antiviral therapy is currently available for DENV. We report here that N-sulfonylanthranilic acid derivatives are allosteric inhibitors of DENV RNA-dependent RNA polymerase (RdRp). The inhibitor was identified through high-throughput screening of one million compounds using a primer extension-based RdRp assay [substrate poly(C)/oligo(G) 20 ]. Chemical modification of the initial "hit" improved the compound potency to an IC 50 (that is, a concentration that inhibits 50% RdRp activity) of 0.7 M. In addition to suppressing the primer extension-based RNA elongation, the compound also inhibited de novo RNA synthesis using a DENV subgenomic RNA, but at a lower potency (IC 50 of 5 M). Remarkably, the observed anti-polymerase activity is specific to DENV RdRp; the compound did not inhibit WNV RdRp and exhibited IC 50 s of >100 M against hepatitis C virus RdRp and human DNA polymerase ␣ and ␤. UV cross-linking and mass spectrometric analysis showed that a photoreactive inhibitor could be cross-linked to Met343 within the RdRp domain of DENV NS5. On the crystal structure of DENV RdRp, Met343 is located at the entrance of RNA template tunnel. Biochemical experiments showed that the order of addition of RNA template and inhibitor during the assembly of RdRp reaction affected compound potency. Collectively, the results indicate that the compound inhibits RdRp through blocking the RNA tunnel. This study has provided direct evidence to support the hypothesis that allosteric pockets from flavivirus RdRp could be targeted for antiviral development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Compound synthesis and structure-activity relationship (SAR) studies were recently published (45). Compound NITD-1 was an initial "hit" identified from a DENV RdRp HTS.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Dengue Virus Polymerase by Blocking of the RNA Tunnel

Niyomrattanakit

Chen

Dong

et al. 2010

J Virol

Self Cite

107

116

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“…Edavorone (197) was introduced in the market by Mitsubishi Pharma in 2001 as a neuroprotective agent (improving neurological recovery following acute brain infarction).…”

Section: 188mentioning

confidence: 99%

A review of recent progress (2002-2012) on the biological activities of pyrazoles

Pérez-Fernández¹,

Goya²,

Elguero³

2013

Arkivoc

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Dedicated to Professor Rosa M. Claramunt on the occasion of her 65 th anniversary AbstractIn this review, we report the structures of 243 pyrazoles with their corresponding biological activities. All of them are represented around the common structure of the pyrazole ring even in those cases where the heterocycle is only a minor part of the molecule. The classification we have used is based on chemical structure considerations and not in terms of the therapeutic area which is the more common approach. Some general conclusions have been drawn linking structures with activities.

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Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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N-Sulfonylanthranilic Acid Derivatives as Allosteric Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase

Cited by 58 publications

References 21 publications

Inhibition of Dengue Virus Polymerase by Blocking of the RNA Tunnel

Inhibition of Dengue Virus Polymerase by Blocking of the RNA Tunnel

A review of recent progress (2002-2012) on the biological activities of pyrazoles

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

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