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Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-15 , DOI: 10.1021/acs.jmedchem.1c00818
Khouloud Chakroun 1, 2 , Marwa Taouai 1, 2 , Vanessa Porkolab 3 , Joanna Luczkowiak 4 , Roman Sommer 5 , Coraline Cheneau 6 , David Mathiron 7 , Mohamed Amine Ben Maaouia 1, 2 , Serge Pilard 7 , Rym Abidi 2 , Catherine Mullié 8 , Franck Fieschi 3 , Peter J Cragg 9 , Franck Halary 6 , Rafael Delgado 4 , Mohammed Benazza 1
Affiliation  

In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann–Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.

中文翻译:

在埃博拉病毒顺式感染和 HCMV-gB 重组糖蛋白与 MDDC 细胞相互作用模型中,基于带异羟肟酸接头的低价杯 [4] 芳烃糖缀合物通过阻断 DC-SIGN 作为强抑制剂

除了各种病毒糖蛋白受体(例如硫酸乙酰肝素、尼曼-皮克 C1 等)外,树突状细胞特异性细胞间粘附分子 3-抓取非整合素 (DC-SIGN),来自 C 型凝集素受体家族,对复制前侵入宿主细胞的多种病毒(例如埃博拉病毒、人类巨细胞病毒 (HCMV)、HIV-1、严重急性呼吸系统综合症冠状病毒 2 等)发挥最重要的致病功能之一;因此,它的抑制代表了一种相关的细胞外抗病毒疗法。我们报告了两种新的p - t Bu-杯芳烃糖簇12,它们带有四异羟肟酸基团,它们对可溶性 DC-SIGN 结合表现出微摩尔抑制,并提供纳摩尔 IC 50通过用埃博拉病毒糖蛋白假型化的病毒颗粒抑制 DC-SIGN 依赖性 Jurkat 顺式细胞感染和 HCMV-gB 重组糖蛋白与表达 DC-SIGN 的单核细胞衍生树突细胞相互作用。糖、接头和杯芳烃核心的独特合作参与可能是 DC-SIGN 对这些低价系统的强大亲和力的背后。我们在此声明了用于合理开发大范围抗病毒疗法的新的有希望的候选物。
更新日期:2021-10-14
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