Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase

Cain, Ricky; Salimraj, Ramya; Punekar, Avinash S.; Bellini, Dom; Fishwick, Colin W. G.; Czaplewski, Lloyd G.; Scott, David J.; Harris, Gemma; Dowson, Christopher G.; Lloyd, Adrian J.; Roper, David I.

doi:10.1021/acs.jmedchem.9b01131

Cited by 7 publications

(6 citation statements)

References 43 publications

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“…A dicationic metal ion, such as Mn 2+ for SerS or Mg 2+ or Zn 2+ reported for other aaRSs, is coordinated in close proximity. These metals span up an octahedral coordination sphere that includes conserved glutamates as well as water molecules and the α and β -phosphate of the primary ATP (Cusack 1995 , Swairjo and Schimmel 2005 , Cain et al 2019 ). In addition, a positively charged amino acid further coordinates the α -phosphate, activating ATP and stabilizing the intermediate aminoacyl-AMP by quenching the emerging charges.…”

Section: Origin Synthesis and Degradation Of Ap4a In Bacteriamentioning

confidence: 99%

The mysterious diadenosine tetraphosphate (AP4A)

et al. 2023

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Dinucleoside polyphosphates, a class of nucleotides found amongst all the Trees of Life, have been gathering a lot of attention in the past decades due to their putative role as cellular alarmones. In particular, diadenosine tetraphosphate (AP4A) has been widely studied in bacteria facing various environmental challenges and has been proposed to be important for ensuring cellular survivability through harsh conditions. Here, we discuss the current understanding of AP4A synthesis and degradation, protein targets, their molecular structure where possible, insights into the molecular mechanisms of AP4A action and its physiological consequences. Lastly, we will briefly touch on what is known with regards to AP4A beyond the Bacterial Kingdom, given its increasing appearance in the Eukaryotic world. Altogether, the notion that AP4A is a conserved second messenger in organisms ranging from bacteria to humans and is able to signal and modulate cellular stress regulation seems promising.

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Section: Origin Synthesis and Degradation Of Ap4a In Bacteriamentioning

confidence: 99%

The mysterious diadenosine tetraphosphate (AP4A)

et al. 2023

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“…Employing structure-based drug design (SBDD) and bioinformatics approaches, a novel series of selective bacterial SerRS inhibitors were synthesized [151] (Figure 10a). Superposing the structures of SSA bound to SerRS from E. coli, S. aureus, and human cytoplasm showed a high degree of similarity, but a small extension in the hydrophobic cavity adjacent to the C2 position of SSA was only present in prokaryotic SerRS and not in human enzymes.…”

Section: Synthetic Bi-substrate Aars Inhibitorsmentioning

confidence: 99%

“…Bioinformatic analysis revealed that the boundary between the canonical catalytic site and this extended pocket is defined by a glycine residue (one residue upstream of the highly conserved class II arginine in motif-3 that is responsible for stacking interaction with the adenine base of ATP) instead of an amino acid with a side chain like threonine in the human homolog. Therefore, the newly designed compounds focus on modification at the C2 position of adenine, based on the SSA chemical framework [151] (Figure 10a).…”

Section: Synthetic Bi-substrate Aars Inhibitorsmentioning

confidence: 99%

Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

Pang

Weeks²

2021

IJMS

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Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets.

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“…2-(hydroxymethyl)-nebularine was reported to exhibit antiviral activity [ 12 ], 2-(hydroxymethyl)inosine monophosphate to inhibit IMP dehydrogenase [ 8 ], and protected 2-(hydroxymethyl)inosine was used in the construction of inhibitors of GMP synthetase [ 9 ]. Interestingly, a recent report of the group of Roper discussed the beneficial effects of, in particular, C2-arylated adenosine congeners as inhibitors of bacterial seryl-tRNA synthetase, attaining selective inhibition with greater than two orders of magnitude compared to that for their human homologue [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors

et al. 2020

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Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N1-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N9-position, we obtained the N3-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N7-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these “base-flipped” analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N3-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N1 and the N6-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis.

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Structure-Guided Enhancement of Selectivity of Chemical Probe Inhibitors Targeting Bacterial Seryl-tRNA Synthetase

Cited by 7 publications

References 43 publications

The mysterious diadenosine tetraphosphate (AP4A)

The mysterious diadenosine tetraphosphate (AP4A)

Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors

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