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

Publication date: Available online 20 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kazuto Shiraishi, Noriko Saito-Tarashima, Yosuke Igata, Keiji Murakami, Yasuko Okamoto, Yoichiro Miyake, Kazuhiro Furukawa, Noriaki Minakawa
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 (34.8 μM), 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.

Graphical abstract

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