Orthogonal Hydroxyl Functionalization of cGAMP Confers Metabolic Stability and Enables Antibody Conjugation.
Orthogonal Hydroxyl Functionalization of cGAMP Confers Metabolic Stability and Enables Antibody Conjugation.
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cGAMP的正交羟基官能化赋予代谢稳定性并使抗体缀合成为可能。
DOI：
10.1021/acscentsci.3c01122
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发表时间：
2023-12-27
影响因子：
18.2
通讯作者：
Chen, Chuo
中科院分区：
文献类型：
--
作者：
Lu, Yong;You, Lin;Li, Liping;Kilgore, Jessica A.;Liu, Shun;Wang, Xiaoyu;Dai, Yuanwei;Wei, Qi;Shi, Heping;Han, Lei;Sun, Lijun;Chen, Zhijian J.;Zhang, Xuewu;Williams, Noelle S.;Chen, Chuo
CGAMP是由cGAS-DNA复合体产生的一种信号分子，通过刺痛建立抗菌和抗肿瘤免疫。虽然STING激活作为一种新的治疗癌症的策略具有潜力，但cGAMP通常被认为不适合在体内使用，因为它的磷酸二酯连接迅速断裂，并且在生理条件下细胞摄取有限。因此，通常采用硫代和氟化来改善cGAMP及其合成类似物的代谢稳定性和通透性。我们现在发现，cGAMP的3‘-羟基的甲基化也提供了代谢的稳定性，2’-羟基的酰化可以直接和选择性地实现，从而实现受体介导的细胞内递送。与硫代和氟化不同，这些修饰不会产生新的立体中心，也不需要费力地合成积木。因此，正交羟基官能化是解决与体内使用cGAMP相关的问题的简单方法。3‘O-甲基化保护cGAMP不受ENPP1的水解，而2’O-酰化使cGAMP容易与抗体结合。
cGAMP is a signaling molecule produced by the cGAS–DNA complex to establish antimicrobial and antitumor immunity through STING. Whereas STING activation holds potential as a new strategy to treat cancer, cGAMP is generally considered unsuitable for in vivo use because of the rapid cleavage of its phosphodiester linkages and the limited cellular uptake under physiological conditions. Consequently, phosphorothioation and fluorination are commonly used to improve the metabolic stability and permeability of cGAMP and its synthetic analogues. We now show that methylation of the 3′-hydroxyl group of cGAMP also confers metabolic stability and that acylation of the 2′-hydroxyl group can be achieved directly and selectively to enable receptor-mediated intracellular delivery. Unlike phosphorothioation and fluorination, these modifications do not create a new stereogenic center and do not require laborious building block synthesis. As such, orthogonal hydroxyl functionalization is a simple solution to issues associated with the in vivo use of cGAMP. 3′O-Methylation protects cGAMP from ENPP1 hydrolysis, and 2′O-acylation enables easy conjugation to an antibody.
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DOI：
10.1039/c3cc45220d
发表时间：
2013-09-25
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Castañeda L;Maruani A;Schumacher FF;Miranda E;Chudasama V;Chester KA;Baker JR;Smith ME;Caddick S
通讯作者：
Caddick S
影响因子：
18.2
作者：
Cordova AF;Ritchie C;Böhnert V;Li L
通讯作者：
Li L
影响因子：
4.7
作者：
Agarwal, Paresh;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
DOI：
10.1016/j.ddtec.2018.09.004
发表时间：
2018-12-01
期刊：
Drug discovery today. Technologies
影响因子：
--
作者：
Forte, Nafsika;Chudasama, Vijay;Baker, James R
通讯作者：
Baker, James R
影响因子：
--
作者：
Cook, P D
通讯作者：
Cook, P D