Replacement of oxygen with sulfur on the furanose ring of cyclic dinucleotides enhances the immunostimulatory effect via STING activation,RSC Medicinal Chemistry

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Replacement of oxygen with sulfur on the furanose ring of cyclic dinucleotides enhances the immunostimulatory effect via STING activation
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-6-18 , DOI: 10.1039/d1md00114k
Noriko Saito-Tarashima ₁ , Mao Kinoshita ₁ , Yosuke Igata ₁ , Yuta Kashiwabara ₁ , Noriaki Minakawa ₁

Affiliation

Cyclic dinucleotides (CDNs) are secondary messengers composed of two purine nucleotides linked via two phosphodiester linkages: c-di-GMP, c-di-AMP, 3′,3′-cGAMP, and 2′,3′-cGAMP. CDNs activate the stimulator of interferon genes (STING) and trigger immune responses in mammalian species. CDNs are thus fascinating molecules as drug candidates, and chemically stable CDN analogues that act as STING agonists are highly desired at present. We herein report the practical synthesis of 4′-thiomodified c-di-AMP analogues, which have sulfur atoms at the 4′-position on the furanose ring instead of oxygen atoms, using simple phosphoramidite chemistry. The resulting 4′-thiomodified c-di-AMP analogues acted as potent STING agonists with long-term activity. Our results show that replacing O4′ on CDNs with sulfur can lead to enhanced immunostimulatory effects via STING activation.

中文翻译：

在环状二核苷酸的呋喃糖环上用硫取代氧通过 STING 激活增强免疫刺激作用

环状二核苷酸 (CDN) 是由两个嘌呤核苷酸通过两个磷酸二酯键：c-di-GMP、c-di-AMP、3',3'-cGAMP 和 2',3'-cGAMP。CDN 激活干扰素基因 (STING) 刺激物并触发哺乳动物物种的免疫反应。因此，CDN 是作为候选药物的迷人分子，目前非常需要充当 STING 激动剂的化学稳定 CDN 类似物。我们在此报告了 4'-硫代修饰的 c-di-AMP 类似物的实际合成，其使用简单的亚磷酰胺化学，在呋喃糖环的 4'-位具有硫原子而不是氧原子。得到的 4'-硫修饰 c-di-AMP 类似物可作为具有长期活性的强效 STING 激动剂。我们的结果表明，用硫代替 CDN 上的 O4' 可以通过STING 激活增强免疫刺激作用。

更新日期：2021-06-18

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