Synthesis and evaluation of c-di-4′-thioAMP as an artificial ligand for c-di-AMP riboswitch

[Display omitted] Cyclic-di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that binds to an RNA receptor called riboswitch and regulates its downstream genes involving cell wall metabolism, ion transport, and spore germination. Therefore, the c-di-AMP riboswitch can be a novel ta...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2017-07, Vol.25 (14), p.3883-3889
Main Authors: Shiraishi, Kazuto, Saito-Tarashima, Noriko, Igata, Yosuke, Murakami, Keiji, Okamoto, Yasuko, Miyake, Yoichiro, Furukawa, Kazuhiro, Minakawa, Noriaki
Format: Article
Language:English
Subjects:
4′-Thioadenosine
4′-ThioRNA
Bacillus subtilis - enzymology
Bacterial Proteins - chemistry
Bacterial Proteins - metabolism
c-di-AMP
Cyclic AMP - chemical synthesis
Cyclic AMP - chemistry
Cyclic AMP - metabolism
In-line probing
Kinetics
Ligands
Nucleic Acid Conformation
Riboswitch
Riboswitch - physiology
Sulfur - chemistry
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Summary:[Display omitted] Cyclic-di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that binds to an RNA receptor called riboswitch and regulates its downstream genes involving cell wall metabolism, ion transport, and spore germination. Therefore, the c-di-AMP riboswitch can be a novel target of antibiotics. In this study, we synthesized c-di-4′-thioAMP (1), which possesses a sulfur atom instead of an oxygen atom in the furanose ring, as a candidate of a bioisoster for natural c-di-AMP. The resulting 1 bound to the c-di-AMP riboswitch with a micromolar affinity (34.8μM), and the phosphodiesterase resistance of 1 was >12-times higher than that of c-di-AMP. Thus, 1 can be considered to be a stable ligand against a c-di-AMP riboswitch.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2017.05.042