Adenosine/guanosine preferring nucleoside ribohydrolase is a distinct, druggable antitrichomonal target

Beck, Sierra; Muellers, Samantha N.; Benzie, Annie Laurie; Parkin, David W.; Stockman, Brian J.

doi:10.1016/j.bmcl.2015.10.030

Cited by 12 publications

(26 citation statements)

References 24 publications

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“…Biodirected fractionation of the extracts allowed the isolation of three bioactive avonoids. Flavonoids are already widely described for their bioactive properties, including those described as inhibitors of nucleoside hydrolases of Trichomonas vaginalis, 17,18 as well as their leishmanicidal activities. 11,[19][20][21] To further elucidate the mechanism of action, we used molecular docking and NMR Saturation Transfer Difference (STD) experiments 22 to analyze the interactions of the isolated active compounds with LdNH.…”

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confidence: 99%

NewLeishmania donovaninucleoside hydrolase inhibitors from Brazilian flora

et al. 2019

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Section: Introductionmentioning

confidence: 99%

NewLeishmania donovaninucleoside hydrolase inhibitors from Brazilian flora

et al. 2019

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“…In the case of AGNH, flavonoids were identified as micromolar inhibitors. 8 However, one limitation of the flavonoid inhibitors identified from this collection of known drugs is their low ligand efficiency (LE) values 11,12 given their large heavy atom counts (HAC). The flavonoid (+)−taxifolin shown in Figure 1 has a LE of 0.34, but its molar mass of 304 g/mol (heavy atom count of 22) combined with only modest micromolar activity makes it a less than ideal chemical starting point for drug design.…”

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confidence: 99%

“…The presence of the 1 H-DMSO signal also does not interfere with reaction monitoring. 8 The utility of this method for fragment screening is demonstrated in Figure 2, which shows the reaction spectra for six mixtures of six compounds each, along with 0 and 40 min control spectra. None of the resonances for the 36 fragments overlap with the substrate resonance at 6.09 ppm or the product resonance at 8.33 ppm.…”

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confidence: 99%

“…This is also supported by the identification of 2-chloro-N(6)-cyclopenty-ladenosine as a 9 μM inhibitor in our previous work. 8 Analogs of fragment 2 shown in Table 2 also provide initial SAR, including the impact of polar functional groups delineated by compounds 12-14. Molecular modeling and X-ray crystallography are being pursued to support structure-guided inhibitor design.…”

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confidence: 99%

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Ligand-Efficient Inhibitors of Trichomonas vaginalis Adenosine/Guanosine Preferring Nucleoside Ribohydrolase

et al. 2019

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Trichomoniasis is caused by the parasitic protozoan Trichomonas vaginalis and is the most prevalent, nonviral sexually transmitted disease. The parasite has shown increasing resistance to the current 5-nitroimidazole therapies indicating the need for new therapies with different mechanisms. T. vaginalis is an obligate parasite that scavenges nucleosides from host cells and then uses salvage pathway enzymes to obtain the nucleobases. The adenosine/guanosine preferring nucleoside ribohydrolase was screened against a 2000-compound diversity fragment library using a 1 H NMR-based activity assay. Three classes of inhibitors with more than five representatives were identified: bis-aryl phenols, amino bicyclic pyrimidines, and aryl acetamides. Among the active fragments were 10 compounds with ligand efficiency values greater than 0.5, including five with IC 50 values <10 μM. Jump-dilution and detergent counter screens validated reversible, targetspecific activity. The data reveals an emerging SAR that is guiding our medicinal chemistry efforts aimed at discovering compounds with nanomolar potency.

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“…The druggability of AGNH and UNH have been tested previously by developing NMR-based activity assays to screen the National Institutes of Health Clinical Compound Collection for inhibitors. Flavonoids were identified as strong inhibitors of AGNH, [21] while the proton pump inhibitors, omeprazole, pantoprazole, and rabeprazole were identified as potent inhibitors of UNH. [22] Both enzymes are now the basis of fragment-based drug discovery projects.…”

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Druggability of the guanosine/adenosine/cytidine nucleoside hydrolase from Trichomonas vaginalis

et al. 2018

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Trichomonas vaginalis infects approximately 300 million people worldwide annually. Infected individuals have a higher susceptibility to more serious conditions such as cervical and prostate cancer. The parasite has developed increasing resistance to current drug therapies, with an estimated 5% of clinical cases resulting from resistant strains, creating the need for new therapeutic strategies with novel mechanisms of action. Nucleoside salvage pathway enzymes represent novel drug targets as these pathways are essential for the parasite's survival. The guanosine/adenosine/cytidine nucleoside hydrolase (GACNH) may be particularly important as its expression is upregulated under glucose-limiting conditions mimicking those that occur during infection establishment. GACNH was screened against the NIH Clinical Collection to explore its druggability. Seven compounds were identified with IC values <20 μM. Extensive overlap was found between inhibitors of GACNH and the adenosine/guanosine nucleoside hydrolase (AGNH), but no overlap was found with inhibitors of the uridine nucleoside hydrolase. The guanosine analog ribavirin was the only compound found to be specific for GACNH. Compounds that inhibit both AGNH and GACNH purine salvage pathway enzymes may prove critical given the role that GACNH appears to play in the early stages of infection.

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Adenosine/guanosine preferring nucleoside ribohydrolase is a distinct, druggable antitrichomonal target

Cited by 12 publications

References 24 publications

NewLeishmania donovaninucleoside hydrolase inhibitors from Brazilian flora

NewLeishmania donovaninucleoside hydrolase inhibitors from Brazilian flora

Ligand-Efficient Inhibitors of Trichomonas vaginalis Adenosine/Guanosine Preferring Nucleoside Ribohydrolase

Druggability of the guanosine/adenosine/cytidine nucleoside hydrolase from Trichomonas vaginalis

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