Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus,Organic & Biomolecular Chemistry

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Polymeric mannosides prevent DC-SIGN-mediated cell-infection by cytomegalovirus
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2017-08-29 00:00:00 , DOI: 10.1039/c7ob01569k
S. Brument _{1,

2,

3,

4,

5} , C. Cheneau _{6,

7,

8,

9,

10} , Y. Brissonnet _{1,

2,

3,

4,

5} , D. Deniaud _{1,

2,

3,

4,

5} , F. Halary _{6,

7,

8,

9,

10} , S. G. Gouin _{1,

2,

3,

4,

5}

Affiliation

Human cytomegalovirus (HCMV) is a beta-herpesvirus with a high prevalence in the population. HCMV is asymptomatic for immunocompetent adults but is a leading cause of morbidity for new born and immunocompromised patients. It was recently shown that the envelope glycoprotein B (gB) of HCMV interacts with the Dendritic Cell-Specific ICAM-3 Grabbing Non integrin (DC-SIGN) to infect the host. In this work we developed a set of DC-SIGN blockers based on mono-, di-, tetra and polyvalent mannosides. The multivalent mannosides were designed to interact with the carbohydrate recognition domains of DC-SIGN in a chelate or bind and recapture process, and represent the first chemical antiadhesives of HCMV reported so far. Polymeric dextrans coated with triazolylheptylmannoside (THM) ligands were highly potent, blocking the gB and DC-SIGN interaction at nanomolar concentrations. The compounds were further assessed for their ability to prevent the DC-SIGN mediated HCMV infection of dendritic cells. A dextran polymer coated with an average of 902 THM ligands showed an outstanding effect in blocking the HCMV trans-infection with IC₅₀ values down to the picomolar range (nanomolar when expressed in THM concentration). Each THM moiety on the polymer surpassed the antiadhesive effect of the methylmannoside reference by more than four orders of magnitude. The compound proved non-cytotoxic at the high concentration of 2 mM and therefore represents an interesting antiadhesive candidate against HCMV and potentially against other virus hijacking dendritic cells to infect the host.

中文翻译：

聚合甘露糖苷可预防巨细胞病毒感染DC-SIGN介导的细胞感染

人类巨细胞病毒（HCMV）是在人群中普遍流行的β疱疹病毒。HCMV对有免疫能力的成年人无症状，但是新生儿和免疫功能低下患者发病的主要原因。最近显示，HCMV的包膜糖蛋白B（gB）与树突状细胞特异性ICAM-3捕获非整联蛋白（DC-SIGN）相互作用，感染宿主。在这项工作中，我们开发了一套基于单价，二价，四价和多价甘露糖苷的DC-SIGN阻滞剂。多价甘露糖苷经设计可在螯合或结合和重新捕获过程中与DC-SIGN的碳水化合物识别结构域相互作用，是迄今为止报道的首批HCMV化学抗粘剂。涂有三唑基庚基甘露糖苷（THM）配体的聚合葡聚糖非常有效，在纳摩尔浓度下阻止gB和DC-SIGN相互作用。进一步评估了化合物预防DC-SIGN介导的树突状细胞的HCMV感染的能力。用平均902 THM配体包被的右旋糖酐聚合物在阻断HCMV方面显示出显着效果IC ₅₀值低至皮摩尔范围的反式感染（当以THM浓度表示时为纳摩尔）。聚合物上的每个THM部分都超过了甲基甘露糖苷参考的抗粘连作用超过四个数量级。该化合物在2 mM的高浓度下被证明是无细胞毒性的，因此代表了一种针对HCMV的潜在抗粘连候选物，并可能针对感染宿主的其他病毒劫持树突状细胞。

更新日期：2017-09-20

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