我国科学家在登革病毒感染血管内皮细胞的分子机制研究中取得重要进展，附文献全文
近日，首都医科大学基础医学院安静教授团队在登革病毒感染血管内皮细胞的分子机制研究中取得重要进展。相关成果“Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with β3 integrin”（来源于登革病毒E蛋白的多肽P4和P7通过与整合素β3相互作用抑制Ⅱ型登革病毒进入）于2018年4月28日在国际学术期刊Antiviral Research在线发表。登革病毒（Dengue virus，DENV）是黄病毒科黄病毒属的单股正链RNA病毒，共包含四种血清型（DENV1-4），由埃及伊蚊和白纹伊蚊叮咬传播，登革病毒感染一般会引起登革热（Dengue fever，DF）和重症登革。重症登革主要是由微血管通透性增加引起的出血、休克以及脏器功能损害，可危及患者生命，但致病机制不明。课题组前期研究发现：广泛存在于血管内皮细胞表面的整合素β3可能作为病毒受体参与DENV2进入血管内皮细胞。在此基础上，课题组在安静教授的指导下，利用膜蛋白酵母双杂交系统及质粒转染实验筛选发现DENV2与整合素β3相互作用的蛋白为E蛋白；利用表面等离子共振技术及多肽合成，进一步明确了E蛋白与整合素β3相互作用的位点主要位于E蛋白Ⅲ区段（EDⅢ）的C333-V347 (P4)和G381-K394 (P7)氨基酸序列。细胞水平实验则证实了来源于相互作用位点的多肽P4和P7对DENV2进入有明显的作用，且呈现剂量依赖关系，其半数抑制浓度分别为19.08 ± 2.52 μM以及12.86 ± 5.96 μM。包含FG-loop结构的多肽P7可同时抑制DENV2和DENV1进入人脐静脉内皮细胞（Human umbilical vein endothelial cell，HUVEC）细胞。以上结果表明整合素β3为DENV2感染内皮细胞的受体或共受体，利用多肽封闭DENV2与整合素β3相互作用位点可以抑制DENV2进入HUVEC细胞。该研究首次揭示了DENV2感染内皮细胞的分子机制，为深入理解重症登革的发病机制提供了理论依据，同时亦为靶向抗病毒药物的研发提供了新思路。
该项课题得到国家自然基金委项目资助。
原文摘要：
Dengue virus (DENV) infection has become a severe public health problem worldwide. However, there is no specific antiviral drug available yet. In this study, we found that DENV serotype 2 (DENV2) infection enhanced the expression of β3 integrin on human umbilical vein endothelial cells (HUVECs) and that DENV2 antigens co-localized with β3 integrin. DENV2 envelope protein (E) directly interacted with β3 integrin, and their interacting sites were located at domain III of E protein (EDIII). Several synthetic peptides were designed based on the amino acid sequence of EDIII, and peptides P4 and P7 could inhibit DENV2 entry into HUVECs in a dose-dependent manner. The inhibitory concentration (IC50) of the two peptides was 19.08 ± 2.52 μM for P4 and 12.86 ± 5.96 μM for P7. Moreover, P7 containing an FG-loop, but not P4, could also inhibit DENV1 entry into HUVECs. Our results suggest a novel mechanism in which interaction between β3 integrin and EDIII is involved in DENV entry. The findings on the inhibitory effect of the peptides on viral entry have significance for anti-DENV drug design 文献下载全文
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