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

European Journal of Medicinal Chemistry
Baole ZhangArthur Van Aerschot

Abstract

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that precisely attach an amino acid to its cognate tRNA. This process, which is essential for protein translation, is considered a viable target for the development of novel antimicrobial agents, provided species selective inhibitors can be identified. Aminoacyl-sulfamoyl adenosines (aaSAs) are potent orthologue specific aaRS inhibitors that demonstrate nanomolar affinities in vitro but have limited uptake. Following up on our previous work on substitution of the base moiety, we evaluated the effect of the N3-position of the adenine by synthesizing the corresponding 3-deazaadenosine analogues (aaS3DAs). A typical organism has 20 different aaRS, which can be split into two distinct structural classes. We therefore coupled six different amino acids, equally targeting the two enzyme classes, via the sulfamate bridge to 3-deazaadenosine. Upon evaluation of the inhibitory potency of the obtained analogues, a clear class bias was noticed, with loss of activity for the aaS3DA analogues targeting class II enzymes when compared to the equivalent aaSA. Evaluation of the available crystallographic structures point to the presence of a conserved water molecule which could have importance for b...Continue Reading

Citations

Jan 24, 2019·The Journal of Biological Chemistry·Christopher S Francklyn, Patrick Mullen
Oct 22, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Baole ZhangArthur Van Aerschot
Nov 30, 2020·European Journal of Medicinal Chemistry·Dries De RuysscherArthur Van Aerschot
Feb 14, 2021·International Journal of Molecular Sciences·Luping PangArthur Van Aerschot

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