Natural products and their derivatives as tRNA synthetase inhibitors and antimicrobial agents

Cochrane, Rachel V. K.; Norquay, Amy; Vederas, John C.

doi:10.1039/c6md00274a

Cited by 22 publications

(18 citation statements)

References 103 publications

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“…Screening of both natural and synthetic molecules for aaRS inhibitors has yielded diverse sets of chemical structures [1,[4][5][6][7]. However, for various reasons only a limited number of compounds have reached the market.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of pyrimidine substituted aminoacyl-sulfamoyl nucleosides as potential inhibitors targeting class I aminoacyl-tRNA synthetases

Nautiyal

Graef

Pang

et al. 2019

European Journal of Medicinal Chemistry

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Aminoacyl-tRNA synthetases (aaRSs) catalyze the ATP-dependent coupling of an amino acid to its cognate tRNA. Being vital for protein translation aaRSs are considered a promising target for the development of novel antimicrobial agents. 5'-O-(N-aminoacyl)-sulfamoyl adenosine (aaSA) is a non-hydrolysable analog of the aaRS reaction intermediate that has been shown to be a potent inhibitor of this enzyme family but is prone to chemical instability and enzymatic modification. In an attempt to improve the molecular properties of this scaffold we synthesized a series of base substituted aaSA analogues comprising cytosine, uracil and N 3-methyluracil targeting leucyl-, tyrosyl-and isoleucyl-tRNA synthetases. In in vitro assays seven out of the nine inhibitors demonstrated K i app values in the low nanomolar range. To complement the biochemical studies, X-ray crystallographic structures of Neisseria gonorrhoeae leucyl-tRNA synthetase and Escherichia coli tyrosyl-tRNA synthetase in complex with the newly synthesized compounds were determined. These highlighted a subtle interplay between the base moiety and the target enzyme in defining relative inhibitory activity. Encouraged by this data we investigated if the pyrimidine congeners could escape a natural resistance mechanism, involving acetylation of the amine of the aminoacyl group by the bacterial Nacetyltransferases RimL and YhhY. With RimL the pyrimidine congeners were less susceptible to inactivation compared to the equivalent aaSA, whereas with YhhY the converse was true. Combined the various insights resulting from this study will pave the way for the further rational design of aaRS inhibitors.

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Section: Introductionmentioning

confidence: 99%

Comparative analysis of pyrimidine substituted aminoacyl-sulfamoyl nucleosides as potential inhibitors targeting class I aminoacyl-tRNA synthetases

Nautiyal

Graef

Pang

et al. 2019

European Journal of Medicinal Chemistry

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“…Aminoacyl-tRNA synthetases (aaRSs) are a class of enzymes that have been validated as antimicrobial targets129, 130, 131, 132. Most aaRS inhibitors are targeted at their synthetic active site by mimicking the endogenous substrate aminoacyl-AMP (aa-AMP) or its stable analogue aminoacylsulfa-moyladenosine (aa-AMS).…”

Section: Structural Simplification Of Bioactive Small Moleculesmentioning

confidence: 99%

Structural simplification: an efficient strategy in lead optimization

Wang

Dong

Sheng

2019

Acta Pharmaceutica Sinica B

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The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding “molecular obesity”. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

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“…They have therefore attracted attention as therapeutic targets for the discovery of broad-spectrum antibacterials. [1][2][3][4] The aaRS enzymes covalently link the cognate amino acid to its transfer RNA (tRNA) as part of protein biosynthesis. Aminoacylation of tRNA is a two-step process in which the enzymes initially form an aminoacyl adenylate intermediate from the amino acid and ATP.…”

Section: Takedownmentioning

confidence: 99%

N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors

Charlton

Aleksis

Saint-Léger

et al. 2018

ACS Med. Chem. Lett.

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-Leucinyl benzenesulfonamides have been discovered as a novel class of potent inhibitors of leucyl-tRNA synthetase. The binding of inhibitors to the enzyme was measured by using isothermal titration calorimetry. This provided information on enthalpy and entropy contributions to binding, which, together with docking studies, were used for structure-activity relationship analysis. Enzymatic assays revealed that-leucinyl benzenesulfonamides display remarkable selectivity for leucyl-tRNA synthetase compared to and human orthologues. The simplest analogue of the series, -leucinyl benzenesulfonamide (R = H), showed the highest affinity against leucyl-tRNA synthetase and also exhibited antibacterial activity against Gram-negative pathogens (the best MIC = 8 μg/mL, ATCC 25922), which renders it as a promising template for antibacterial drug discovery.

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Natural products and their derivatives as tRNA synthetase inhibitors and antimicrobial agents

Abstract: The tRNA synthetase enzymes are promising targets for development of therapeutic agents against infections by parasitic protozoans (e.g. malaria), fungi and yeast, as well as bacteria resistant to current antibiotics.

Cited by 22 publications

References 103 publications

Comparative analysis of pyrimidine substituted aminoacyl-sulfamoyl nucleosides as potential inhibitors targeting class I aminoacyl-tRNA synthetases

Comparative analysis of pyrimidine substituted aminoacyl-sulfamoyl nucleosides as potential inhibitors targeting class I aminoacyl-tRNA synthetases

Structural simplification: an efficient strategy in lead optimization

N-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors

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