Janus-Type核苷类似物拮抗单纯疱疹病毒感染的分子位点及其作用机制研究

Herpes virus infection with the characteristics of high morbidity, long latency and easy to relapse, have been becoming serious threats to human health and public security, but these treatment agents bear various flaws such as low bioavailability, resistance and limited number of targets. Therefore, the proposer designed and synthesized the Janus -type nucleoside analogues, found it can form supramolecular structures by self-assembling (Nature Communications, Most Read Article), showed strong against herpes simplex virus (HSV) activity, but its molecular targets and mechanisms of the antiviral effect remains to be further elucidated. Therefore, this project is through the establishment of oral mucosa epithelial cells after HSV infection model, 1) the whole genome sequencing method is adopted to detect virus gene mutation frequency, biological mass spectrometry compounds is mixed with viral DNA/RNA, to explore its lethal mutation mechanism; 2) Taking oral epithelial cells and virus DNA polymerase, determination parameters enzyme activity of the compounds, and observation the interaction of protein and small molecular, exploring the key groups and amino acid residues, and illustrating the role of molecular targets;3) To optimize the compounds structure;4) To study the toxicity by cells and animal experiments in vivo and in vitro. The above research, not only help to develop the new, high-efficiency, against HSV infection drugs, at the same time, also has the potential for application to other acute viral diseases, plays an important role in the national strategic reserves.

单纯疱疹病毒感染累积面广,发病率高,具癌变可能,对人类健康构成威胁,治疗此类疾病的药物存在毒性大、利用度低、易耐药等亟待解决问题。因此,申请人设计并合成了Janus-Type核苷类似物,发现其能自组装形成超分子结构(Nature Communications),发挥较强的抗单纯疱疹病毒活性,但其抗病毒分子靶点和机制仍需进一步阐明。为此,本项目拟通过建立口腔黏膜上皮细胞HSV感染模型后,1)采用测序法检测病毒基因突变频率,质谱法考察化合物是否掺入病毒DNA/RNA,探索其可能的诱导病毒致死突变机制;2)提取DNA聚合酶后，测定化合物酶活参数,并通过蛋白/小分子交互作用寻找分子靶点,阐明作用机制;3)引入活性基团优化其结构;4)通过细胞和动物实验研究其体内外毒性。上述研究,不仅有助于开发出新型高效低毒的抗HSV感染药物,同时,也有开发应用于突发性病毒性疾病的潜力,对国家的战略储备具有重大意义。

由单纯疱疹病毒1型（Herpes Simplex Virus-1, HSV-1）感染导致的脑炎如果不及时治疗可能会危及生命。单纯疱疹是常见的人类疱疹之一，是由HSV感染引起的皮肤黏膜感染性疾病，对人类的健康和生活质量构成了严重的威胁。因此，对于抗疱疹病毒药物的研究具有很重要的意义。在前期工作中，我们合成一系列Janus-type双面碱基核苷，发现其部分衍生物具有抗病毒活性。为了开发出高效低毒的抗病毒先导化合物，我们在现有的Janus-type双面碱基核苷基础上，对其结构进行结构优化。在研究过程中，我们还发现一类具有良好抗病毒活性的嘧啶肟衍生物。通过构建多种病毒的体外感染模型，我们对Janus-type双面碱基核苷和嘧啶肟衍生物的抗病毒活性、广谱抗病毒活性以及构效关系作了系统性研究，得到了一系列具有高效低毒单纯疱疹病毒1型且具有广谱抗病毒活性的先导化合物，并找到了该类化合物的主要药效基团和分子位点，为后期抗病毒先导化合物的开发奠定了坚实的基础。.

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