Family-wide analysis of aminoacyl-sulfamoyl-3-deazaadenosine analogues as inhibitors of aminoacyl-tRNA synthetases

Zhang, Baole; Graef, S. De; Nautiyal, Manesh; Pang, Liuqing; Gadakh, Bharat; Froeyen, Matheus; Mellaert, Lieve Van; Strelkov, S.V.; Weeks, S.D.

doi:10.1016/j.ejmech.2018.02.013

Cited by 18 publications

(45 citation statements)

References 45 publications

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“…1b-c), a feature that has previously been described in class II synthetase enzymes. 23 In SaSerRS the octahedral coordination of a magnesium ion (Fig 1c) is observed in the active site via Glu349,the SerSA sulfone and water molecules, reminiscent of the magnesium ion observed in both the Candida albicans SerRS and HsSerRS.…”

Section: Crystal Structures Of Serrs In Complex With Sersa Inhibitormentioning

confidence: 92%

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Cain¹,

Salimaraj²,

Punekar³

et al. 2019

Preprint

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Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.

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Section: Crystal Structures Of Serrs In Complex With Sersa Inhibitormentioning

confidence: 92%

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Cain¹,

Salimaraj²,

Punekar³

et al. 2019

Preprint

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“…Despite the failure to obtain a "breakthrough" lead compound by this approach, an important conclusion from these studies is that use of advanced modeling and theory tools such as quantum mechanical chemical calculations can provide additional insights into the interactions of these compounds with ARS active sites, thereby rationalizing the significant differences in Class I versus Class II ARS-targeted compounds (74). Such approaches extend the insights from existing ARSinhibitor complexes, whose numbers are growing in the RCSB Protein Database.…”

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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“…The first approach involved the coupling of different lipophilic groups to the N 6 -amino group of aaSA ( Figure 1). As observed from the crystal structures of Thermus thermophilus (Tt) isoleucine tRNA synthetase (IleRS) in complex with isoleucylsulfamoyl adenosine (ISA) or with mupirocin (ileRS inhibitor; unpublished work), there is sufficient space available around the adenine base to accommodate some chemical modifications [22,23]. In addition, the N 6 -amine is only making one hydrogen bond interaction with the backbone of the protein chain.…”

Section: Design Rationalementioning

confidence: 99%

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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Family-wide analysis of aminoacyl-sulfamoyl-3-deazaadenosine analogues as inhibitors of aminoacyl-tRNA synthetases

Cited by 18 publications

References 45 publications

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase

Progress and challenges in aminoacyl-tRNA synthetase-based therapeutics

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

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