Structural and kinetic analyses of holothurian sulfated glycans suggest potential treatment for SARS-CoV-2 infection.
Structural and kinetic analyses of holothurian sulfated glycans suggest potential treatment for SARS-CoV-2 infection.
复制标题
DOI：
10.1016/j.jbc.2021.101207
复制
发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Pomin VH
中科院分区：
文献类型：
--
作者：
Dwivedi R;Samanta P;Sharma P;Zhang F;Mishra SK;Kucheryavy P;Kim SB;Aderibigbe AO;Linhardt RJ;Tandon R;Doerksen RJ;Pomin VH
某些磺化聚糖，包括来自海洋的聚糖，可以显示出对SARS-CoV-2的潜在影响。本文从海参Pentacta pygmaea (PpFucCS) （MW ~ 10-60 kDa）中分离出一种新的聚焦硫酸软骨素（FucCS），并通过NMR对其进行了结构表征。PpFucCS由{→3)-β-GalNAcX -(1→4)-β-GlcA -[(3→1)Y](1→},X = 4 S(80%)、6 S(10%)或nonsulfated (10%), Y =α-Fuc2, 4 S(40%),α-Fuc2, 4 S -(1→4)-α-Fuc(30%)、或α-Fuc4S(30%),和S = SO3−。比较了PpFucCS以及从褐条异stichopus badionotus中分离的FucCS和硫酸化fucan （IbFucCS和IbSF）与肝素的抗sars - cov -2活性。IC50值表明，三种海螺硫酸聚糖的活性比肝素高12倍，没有细胞毒性作用。野生型SARS-CoV-2刺突蛋白受体结合域（spike -protein receptor-binding domain， RBD）和N501Y突变体RBD与肝素固定化传感器芯片相互作用的表面等离子体共振得到的解离常数（KD）分别为94和1.8 × 103 nM。PpFucCS、IbFucCS和IbSF对肝素与野生型s蛋白结合的竞争性表面等离子体共振抑制分析显示，IC50值（在纳mol范围内）分别是肝素的6倍、25倍和6倍。计算模拟的数据表明，Fuc单元的硫酸化模式影响了与GlcA的氢键，并且在s蛋白RBD结合时发生了一些低聚糖结构的构象变化。与肝素相比，IbSF的抗凝作用可以忽略不计。我们的研究结果表明，IbSF可能是未来研究SARS-CoV-2的一个有希望的分子。
Certain sulfated glycans, including those from marine sources, can show potential effects against SARS-CoV-2. Here, a new fucosylated chondroitin sulfate (FucCS) from the sea cucumber Pentacta pygmaea (PpFucCS) (MW ∼10–60 kDa) was isolated and structurally characterized by NMR. PpFucCS is composed of {→3)-β-GalNAcX-(1→4)-β-GlcA-[(3→1)Y]-(1→}, where X = 4S (80%), 6S (10%) or nonsulfated (10%), Y = α-Fuc2,4S (40%), α-Fuc2,4S-(1→4)-α-Fuc (30%), or α-Fuc4S (30%), and S = SO3−. The anti-SARS-CoV-2 activity of PpFucCS and those of the FucCS and sulfated fucan isolated from Isostichopus badionotus (IbFucCS and IbSF) were compared with that of heparin. IC50 values demonstrated the activity of the three holothurian sulfated glycans to be ∼12 times more efficient than heparin, with no cytotoxic effects. The dissociation constant (KD) values obtained by surface plasmon resonance of the wildtype SARS-CoV-2 spike (S)-protein receptor-binding domain (RBD) and N501Y mutant RBD in interactions with the heparin-immobilized sensor chip were 94 and 1.8 × 103 nM, respectively. Competitive surface plasmon resonance inhibition analysis of PpFucCS, IbFucCS, and IbSF against heparin binding to wildtype S-protein showed IC50 values (in the nanomolar range) 6, 25, and 6 times more efficient than heparin, respectively. Data from computational simulations suggest an influence of the sulfation patterns of the Fuc units on hydrogen bonding with GlcA and that conformational change of some of the oligosaccharide structures occurs upon S-protein RBD binding. Compared with heparin, negligible anticoagulant action was observed for IbSF. Our results suggest that IbSF may represent a promising molecule for future investigations against SARS-CoV-2.
登录
查看更多内容
影响因子：
64.5
作者：
Clausen, Thomas Mandel;Sandoval, Daniel R.;Esko, Jeffrey D.
通讯作者：
Esko, Jeffrey D.
影响因子：
7.7
作者：
Zamorano Cuervo N;Grandvaux N
通讯作者：
Grandvaux N
影响因子：
11.2
作者：
Gong, Pi-Xian;Li, Qin-Ying;Li, Hui-Jing
通讯作者：
Li, Hui-Jing
影响因子：
11.2
作者：
Chen, Shiguo;Xue, Changhu;Chai, Wengang
通讯作者：
Chai, Wengang
影响因子：
4.8
作者：
Farias, WRL;Valente, AP;Mourao, PAS
通讯作者：
Mourao, PAS