c-di-4'-硫代腺苷酸作为环二腺苷酸核糖开关人工配体的合成与评价
Synthesis and evaluation of c-di-4'-thioAMP as an artificial ligand for c-di-AMP riboswitch.
作者信息
Shiraishi Kazuto, Saito-Tarashima Noriko, Igata Yosuke, Murakami Keiji, Okamoto Yasuko, Miyake Yoichiro, Furukawa Kazuhiro, Minakawa Noriaki
机构信息
Graduate School of Pharmaceutical Science, Tokushima University, 1-78-1 Shomachi, Tokushima 770-8505, Japan.
Department of Oral Microbiology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan.
出版信息
Bioorg Med Chem. 2017 Jul 15;25(14):3883-3889. doi: 10.1016/j.bmc.2017.05.042. Epub 2017 May 20.
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.
环二磷酸腺苷（c-di-AMP）是一种细菌第二信使，它与一种名为核糖开关的RNA受体结合，并调节其涉及细胞壁代谢、离子转运和孢子萌发的下游基因。因此，c-di-AMP核糖开关可以成为抗生素的新靶点。在本研究中，我们合成了c-二-4'-硫代腺苷酸（1），其在呋喃糖环中具有一个硫原子而非氧原子，作为天然c-di-AMP的生物电子等排体候选物。所得的1以微摩尔亲和力（34.8μM）与c-di-AMP核糖开关结合，且1的磷酸二酯酶抗性比c-di-AMP高12倍以上。因此，1可被认为是针对c-di-AMP核糖开关的稳定配体。
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