7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.
7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.
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DOI：
10.1021/acscentsci.0c01589
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发表时间：
2021-02-24
影响因子：
18.2
通讯作者：
Withers SG
中科院分区：
文献类型：
--
作者：
Geissner A;Baumann L;Morley TJ;Wong AKO;Sim L;Rich JR;So PPL;Dullaghan EM;Lessard E;Iqbal U;Moreno M;Wakarchuk WW;Withers SG
治疗性糖蛋白在循环系统内的维持在很大程度上与作为聚糖上的末端糖的唾液酸的完整性相关。糖蛋白去唾液酸化，无论是通过自发切割或通过宿主唾液酸酶，导致蛋白质清除，主要是通过肝脏。因此，最低限度修饰的抗水解但生物等效的唾液酸的安装应导致增加的循环半衰期和改善的药代动力学特征。在这里，我们描述了CMP-唾液酸糖供体的化学酶促合成，在7位上带有氟原子，从相应的4-脱氧-4-氟-N-乙酰基己糖胺前体开始。对于具有天然立体化学的衍生物，我们观察到通过唾液酸转移酶的有效糖基转移，沿着所得7-氟唾液酸苷对自发水解（3- 5倍）和对GH 33唾液酸酶裂解（40- 250倍）的稳定性提高。利用唾液酸转移酶快速转移7-氟唾液酸的优点，我们设计了干扰素α-2b的O-聚糖和治疗性糖蛋白α1-抗胰蛋白酶的N-聚糖。HepG 2肝细胞对糖工程化α1-抗胰蛋白酶的摄取研究表明，7-氟唾液酸与唾液酸在抑制与肝细胞凝集素的相互作用方面具有生物等效性。体内药代动力学研究表明，在小鼠循环系统中，相对于未修饰的唾液酸，修饰有7-氟唾液酸的蛋白质的半衰期延长。7-因此，氟唾液酸化作为延长糖蛋白循环半衰期的一种手段提供了相当大的希望，并可能为治疗用途的生物改善剂铺平道路。7-氟唾液酸化作为延长糖蛋白循环半衰期的一种手段提供了相当大的希望，并可能为治疗用途的生物改善剂铺平道路。
The maintenance of therapeutic glycoproteins within the circulatory system is associated, in large part, with the integrity of sialic acids as terminal sugars on the glycans. Glycoprotein desialylation, either by spontaneous cleavage or through host sialidases, leads to protein clearance, mainly through the liver. Thus, the installation of minimally modified sialic acids that are hydrolysis-resistant yet biologically equivalent should lead to increased circulatory half-lives and improved pharmacokinetic profiles. Here we describe the chemoenzymatic synthesis of CMP–sialic acid sugar donors bearing fluorine atoms at the 7-position, starting from the corresponding 4-deoxy-4-fluoro-N-acetylhexosamine precursors. For the derivative with natural stereochemistry we observe efficient glycosyl transfer by sialyltransferases, along with improved stability of the resultant 7-fluorosialosides toward spontaneous hydrolysis (3- to 5-fold) and toward cleavage by GH33 sialidases (40- to 250-fold). Taking advantage of the rapid transfer of 7-fluorosialic acid by sialyltransferases, we engineered the O-glycan of Interferon α-2b and the N-glycans of the therapeutic glycoprotein α1-antitrypsin. Studies of the uptake of the glyco-engineered α1-antitrypsin by HepG2 liver cells demonstrated the bioequivalence of 7-fluorosialic acid to sialic acid in suppressing interaction with liver cell lectins. In vivo pharmacokinetic studies reveal enhanced half-life of the protein decorated with 7-fluorosialic acid relative to unmodified sialic acid in the murine circulatory system. 7-Fluorosialylation therefore offers considerable promise as a means of prolonging circulatory half-lives of glycoproteins and may pave the way toward biobetters for therapeutic use. 7-Fluorosialylation offers considerable promise as a means of prolonging circulatory half-lives of glycoproteins and may pave the way toward biobetters for therapeutic use.
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影响因子：
5.6
作者：
BOSSARTWHITAKER, P;CARSON, M;AIR, GM
通讯作者：
AIR, GM
影响因子：
4.3
作者：
Kao, YH;Lerner, L;Warner, TG
通讯作者：
Warner, TG
影响因子：
3.2
作者：
Indurugalla, Deepani;Watson, Jacqueline N.;Bennet, Andrew J.
通讯作者：
Bennet, Andrew J.
DOI：
10.1073/pnas.1019266108
发表时间：
2011-05-03
影响因子：
11.1
作者：
Lindhout, Theresa;Iqbal, Umar;Wakarchuk, Warren W.
通讯作者：
Wakarchuk, Warren W.
影响因子：
8.6
作者：
Du, Ting;Buenbrazo, Nakita;Wakarchuk, Warren
通讯作者：
Wakarchuk, Warren