<i>N</i>-Leucinyl Benzenesulfonamides as Structurally Simplified Leucyl-tRNA Synthetase Inhibitors

Charlton, M.; Aleksis, Rihards; Saint-Léger, Adélaïde; Gupta, Arya; Loza, Einars; Pouplana, Lluı́s Ribas de; Kaula, Ilze; Gustina, Daina; Madre, Marina; Lola, Daina; Jaudzems, Kristaps; Edmund, Grace; Randall, Chris; Kime, Louise; O’Neill, Alex J.; Goessens, W. H. F.; Jirgensons, Aigars; Finn, Paul W.

doi:10.1021/acsmedchemlett.7b00374

Cited by 16 publications

(14 citation statements)

References 20 publications

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“…To address some of these issues, various efforts were made to modify the aaSA scaffold to obtain analogues with a better activity profile. Such approaches include the modification or shortening of the sulfur-based linker [14], substitution of the sugar ring [15] or the adenine base [16,17]. In the latter case, Cubist Pharmaceuticals (now Merck) reported C-nucleosides where the adenine was replaced with either a functionalized thiazole [18] or ethyl-linked tetrazole derivatives [19] (Fig.…”

Section: Introductionmentioning

confidence: 99%

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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%

“…recently,Charlton et al reported modified N-leucinyl benzenesulfonamides targeting leuRS[15]. This is only a small overview of all available compounds, yet what they have in common is strong inhibitory activity in spite of a large variety of base modifications.…”

mentioning

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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“…Obviously however, selectivity in inhibiting the bacterial aaRS is another issue in development of the aaSA compounds, only dealt with in this work in using the nitrobenzylated prodrug. But the feasibility of selective targeting has been shown previously by the availability of two marketed drugs inhibiting an aaRS, with mupirocin (likewise equipped with a long aliphatic tail) and tavaborole, and in using heterocyclic sulfonamide scaffolds [41,42]. Our extensive 3D structural work [33] on various aaRS in complex with inhibitory ligands (including unpublished work) will further pave the way for improved selectivity.…”

Section: Discussionmentioning

confidence: 93%

Synthesis and Biological Evaluation of Lipophilic Nucleoside Analogues as Inhibitors of Aminoacyl-tRNA Synthetases

et al. 2019

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Emerging antibiotic resistance in pathogenic bacteria and reduction of compounds in the existing antibiotics discovery pipeline is the most critical concern for healthcare professionals. A potential solution aims to explore new or existing targets/compounds. Inhibition of bacterial aminoacyl-tRNA synthetase (aaRSs) could be one such target for the development of antibiotics. The aaRSs are a group of enzymes that catalyze the transfer of an amino acid to their cognate tRNA and therefore play a pivotal role in translation. Thus, selective inhibition of these enzymes could be detrimental to microbes. The 5′-O-(N-(L-aminoacyl)) sulfamoyladenosines (aaSAs) are potent inhibitors of the respective aaRSs, however due to their polarity and charged nature they cannot cross the bacterial membranes. In this work, we increased the lipophilicity of these existing aaSAs in an effort to promote their penetration through the bacterial membrane. Two strategies were followed, either attaching a (permanent) alkyl moiety at the adenine ring via alkylation of the N6-position or introducing a lipophilic biodegradable prodrug moiety at the alpha-terminal amine, totaling eight new aaSA analogues. All synthesized compounds were evaluated in vitro using either a purified Escherichia coli aaRS enzyme or in presence of total cellular extract obtained from E. coli. The prodrugs showed comparable inhibitory activity to the parent aaSA analogues, indicating metabolic activation in cellular extracts, but had little effect on bacteria. During evaluation of the N6-alkylated compounds against different microbes, the N6-octyl containing congener 6b showed minimum inhibitory concentration (MIC) of 12.5 µM against Sarcina lutea while the dodecyl analogue 6c displayed MIC of 6.25 µM against Candida albicans.

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“…More recently, the IBI approach has been augmented by exploring modifications to the basic chemical framework, employing in silico modeling against ARS active sites as a screening tool to tailor functional group changes. Recent examples include inhibitors of ThrRS and LeuRS, which featured a benzene sulfonamide core and extra substituents that confer Table 1 Natural product and synthetic inhibitors of aminoacyl-tRNA synthetases JBC REVIEWS: Aminoacyl-tRNA synthetase as therapeutic targets specificity for the ARS amino acid-binding pockets (72,73). In the case of the compounds targeting LeuRS, the benzene sulfonamide scaffold was improved by docking simulations employing the E. coli LeuRS structure and by the use of isothermal titration calorimetry to assess binding affinity.…”

Section: Identification Of Antibiotic Leads Derived From Ars Inhibitomentioning

confidence: 99%

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

Francklyn

Mullen

2019

Journal of Biological Chemistry

111

104

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Edited by Karin Musier-Forsyth Aminoacyl-tRNA synthetases (ARSs) are universal enzymes that catalyze the attachment of amino acids to the 3 ends of their cognate tRNAs. The resulting aminoacylated tRNAs are escorted to the ribosome where they enter protein synthesis. By specifically matching amino acids to defined anticodon sequences in tRNAs, ARSs are essential to the physical interpretation of the genetic code. In addition to their canonical role in protein synthesis, ARSs are also involved in RNA splicing, transcriptional regulation, translation, and other aspects of cellular homeostasis. Likewise, aminoacylated tRNAs serve as amino acid donors for biosynthetic processes distinct from protein synthesis, including lipid modification and antibiotic biosynthesis. Thanks to the wealth of details on ARS structures and functions and the growing appreciation of their additional roles regulating cellular homeostasis, opportunities for the development of clinically useful ARS inhibitors are emerging to manage microbial and parasite infections. Exploitation of these opportunities has been stimulated by the discovery of new inhibitor frameworks, the use of semi-synthetic approaches combining chemistry and genome engineering, and more powerful techniques for identifying leads from the screening of large chemical libraries. Here, we review the inhibition of ARSs by small molecules, including the various families of natural products, as well as inhibitors developed by either rational design or highthroughput screening as antibiotics and anti-parasitic therapeutics.

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

Cited by 16 publications

References 20 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

Synthesis and Biological Evaluation of Lipophilic Nucleoside Analogues as Inhibitors of Aminoacyl-tRNA Synthetases

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

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