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1. chinaXiv:202002.00081 [pdf]

SARS-coronavirus-2 nsp13 possesses NTPase and RNA helicase activities

Shu, Ting; Huang, Muhan; Wu, Di; Ren, Yujie; Zhang, Xueyi; Han, Yang; Mu, Jingfang; Wang, Ruibing; Qiu, Yang; Zhang, Ding-Yu; Zhou, Xi
Subjects: Biology >> Virology

The ongoing outbreak of Coronavirus Disease 2019 (COVID-19) has become a global pandemic and crisis. SARS-coronavirus-2 (SARS-CoV-2), the causative pathogen of COVID-19, is a positive-sense single-stranded RNA virus belonging to the family Coronaviridae. For RNA viruses, virus-encoded RNA helicases have long been recognized to play pivotal roles during viral life cycles by facilitating the correct folding and replication of viral RNAs. Here, our studies show that SARS-CoV-2-encoded nonstructural protein 13 (nsp13) possesses the nucleoside triphosphate hydrolase (NTPase) and RNA helicase activities that can hydrolyze all types of NTPs and unwind RNA helices dependently of the presence of NTP, and further characterize the biochemical characteristics of these two enzymatic activities associated with SARS-CoV-2 nsp13. Moreover, we found that some bismuth salts could effectively inhibit both the NTPase and RNA helicase activities of SARS-CoV-2 nsp13 in a dose-dependent manner. Thus, our findings demonstrate the NTPase and helicase activities of SARS-CoV-2 nsp13, which may play an important role in SARS-CoV-2 replication and serve as a target for antivirals.

submitted time 2020-04-19 Hits15585Downloads1540 Comment 0

2. chinaXiv:202003.00046 [pdf]

Cryo-EM structure of SARS-CoV spike glycoprotein in post-fusion state

Fan, Xiaoyi; Cao, Duanfang; Kong, Lingfei; Zhang, Xinzheng
Subjects: Biology >> Virology

冠状病毒SARS-CoV,MERS-CoV和新发现的2019-nCoV所引发的传染性疾病严重威胁着人类的生命健康安全。位于冠状病毒表面的spike(S)糖蛋白在病毒传播及感染过程中负责结合宿主细胞受体,融合细胞中的膜结构等关键步骤,是病毒重要的药物靶点。其中在冠状病毒中高度保守的S2亚基作为融膜机器,介导了病毒与宿主之间的膜融合过程。我们运用冷冻电镜单颗粒三维重构技术解析了SARS-CoV S糖蛋白的融膜后构象的结构,展示了S2亚基在融膜过程中的结构特点和构象变化。结合保守性比对和糖基化修饰指认,这项工作分析了位于S2亚基的潜在药物靶点,有益于相关疫苗和药物的开发和设计。

submitted time 2020-03-06 Hits13733Downloads1747 Comment 0

3. chinaXiv:202002.00070 [pdf]

Towards an effective mRNA vaccine against 2019-nCoV: demonstration of virus-like particles expressed from a modified mRNA cocktail

Xia, Jia; Lu, Guoliang; Lu, Jing; Zhang, Jiahui; Feng, Lin; Wang, Bing; Yu, Hang; Xu, Yingjie; Lin, Jinzhong
Subjects: Biology >> Virology

Frequent outbreaks of coronavirus make the development of an effective vaccine imperative. Recently, vaccines based on in-vitro transcribed messenger RNA (mRNA) have shown great potential. The streamlined manufacturing of mRNA molecules, combined with the superior flexibility in the antigen screening, greatly accelerates the development process. When using an mRNA platform to develop a vaccine, initial antigen choice plays a crucial role in determining the final efficacy and safety of the vaccine. Furthermore, mRNA sequences that encode antigens require extensive optimization to ensure highly efficient and sustained expression. Our ongoing efforts to develop an effective mRNA vaccine against 2019-nCoV place emphasis on the virus-like particles (VLPs) as the presenting antigen. At the same time, our second fast track uses mRNA to express the receptor-binding domain of the spike protein(S-RBD). After extensive optimization, an mRNA cocktail containing three genes is able to produce 2019-nCoV virus-like particles highly similar to the native 2019-nCoV. Meanwhile, an mRNA vaccine candidate expressing S-RBD is being tested in mice for its immunogenicity. We will next compare both the efficacy and the safety of the two mRNA vaccines based on S-RBD and VLPs, respectively.

submitted time 2020-02-25 Hits12663Downloads1811 Comment 0

4. chinaXiv:202002.00061 [pdf]

2019新型冠状病毒核衣壳蛋白N能发挥病毒编码的RNAi抑制子功能

Mu, Jingfang; Xu, Jiuyue; Shu, Ting; Wu, Di; Huang, Muhan; Ren, Yujie; Li, Xufang; Geng, Qing; Xu, Yi; Qiu, Yang; Zhou, Xi
Subjects: Biology >> Virology

新型冠状病毒肺炎目前仍在武汉和中国其他地区持续。在目前的形势下,进一步了解新型冠状病毒(SARS-CoV-2)的病毒学和病毒与宿主的相互作用,对控制感染、开发有效的治疗方法具有重要意义。RNA干扰(RNA interference,RNAi)是一种进化上保守的真核生物抗病毒免疫机制,目前已发现许多病毒编码自身的RNA干扰抑制因子作为对抗措施。在这项研究中,我们发现SARS-CoV-2编码的核衣壳蛋白(N)有效地抑制了shRNAs或siRNAs触发的RNAi。此外,与许多由其他病毒编码的VSR类似,SARS-CoV-2的VSR在体外与人类细胞中与dsRNA相互作用,显示出双链RNA(dsRNA)结合活性。综上所述,我们的研究结果表明,SARS-CoV-2的N蛋白在人类细胞中表现出VSR活性,这可能是新型冠状病毒的一个关键免疫逃避因子。

submitted time 2020-02-22 Hits8805Downloads1233 Comment 0

5. chinaXiv:202002.00009 [pdf]

一种新型冠状病毒肺炎(COVID-19)药物与天然产物快速发现的计算药理学方法

全源; 梁峰吉; 熊江辉
Subjects: Biology >> Virology

新发传染病爆发流行期间,亟需提出候选药物功效与机制的科学假说。疫苗或新药研发均需要一定时间,因而药物重定位(老药新用)策略有其独特价值。但是新发疾病其病原体、宿主反应的临床数据不充分,制约了候选药物假设的提出。此阶段常根据病人临床特征进行广谱抗病毒药物的尝试。本文借鉴人工智能领域常见的启发式搜索思路,提出一种新方法(aCODE),基于前期有一定疗效提示的广谱抗病毒药,获得其宿主靶蛋白集合,在全基因组尺度上搜索与之相关性最高的基因模块组合,进而对候选化合物(如已批准上市药物、天然产物)进行模式匹配与统计检验排序。本方法可根据临床实践的进展更新输入药物,迭代输出更精准结果,输出的天然产物或中药、药食同源成分结合其它信息后可实施快速测试,形成敏捷研发测试闭环。本方法的第二版更新及其与文献证据的比对分析请参考:http://chinaxiv.org/abs/202002.00024。

submitted time 2020-02-21 Hits25560Downloads2289 Comment 0

6. chinaXiv:202002.00033 [pdf]

Decoding evolution and transmissions of novel pneumonia coronavirus using the whole genomic data

Yu, Wen-Bin; Tang, Guang-Da; Zhang, Li; Corlett, Richard T.
Subjects: Biology >> Virology
Subjects: Biology >> Genetics

Background. The outbreak of COVID-19 started in mid-December 2019 in Wuhan, Central China. Up to February 18, 2020, SARS-CoV-2 has infected more than 70,000 people in China, and another 25 countries across five continents. In this study, we used 93 complete genomes of SARS-CoV-2 from the GISAID EpiFluTM database to decode the evolution and human-to-human transmissions of SARS-CoV-2 in the recent two months. Methods. Alignment of coding-regions was conducted haplotype analyses using DnaSP. Substitution sites were analyzed in codon. Evolutionary analysis of haplotypes used NETWORK. Population size changes were estimated using both DnaSP and Arlequin. Expansion date of population size was calculated based on the expansion parameter tau (τ) using the formula t=τ/2u. Findings. Eight coding-regions have 120 substitution sites, including 79 non-synonymous and 40 synonymous substitutions. Forty-two non-synonymous substitutions changed the biochemical property of amino acids. No evident combination was found. Fifty-eight haplotypes were classified as five groups, and 31 haplotypes were found in samples from both China and other countries, respectively. The rooted network suggested H13 and H35 to be ancestral haplotypes, and H1 (and its descendent haplotypes including all samples from the Hua Nan market) was derived H3 haplotype. Population size of SARS-CoV-2 were estimated to have a recent expansion on 6 January 2020, and an early expansion on 8 December 2019. Interpretation. Genomic variations of SARS-CoV-2 are still low in comparisons with published genomes of SARS-CoV and MERS-CoV. Phyloepidemiologic analyses indicated the SARS-CoV-2 source at the Hua Nan market should be imported from other places. The crowded market boosted SARS-CoV-2 rapid circulations in the market and spread it to the whole city in early December 2019. Furthermore, phyloepidemiologic approaches have recovered specific direction of human-to-human transmissions, and the import sources of international infectious cases.

submitted time 2020-02-21 Hits289423Downloads73304 Comment 0

7. chinaXiv:202002.00004 [pdf]

武汉2019冠状病毒S蛋白可能存在Furin蛋白酶切位点

李鑫; 段广有; 张伟; 施劲松; 陈嘉源; 陈舜梅; 高山; 阮吉寿
Subjects: Biology >> Virology

摘要:2019年12月,中国武汉报道了2019新型冠状病毒(2019 novel Coronavirus,2019-nCoV)引起的肺炎。基于基因组信息,我们前期研究结果显示2019-nCoV与SARS冠状病毒虽然同属于Beta冠状病毒B亚群(BB冠状病毒),但两种病毒差异很大,这一结果与两者临床症状差异一致。前期研究还发现了BB冠状病毒存在大量的可变翻译,并从分子水平揭示了BB冠状病毒变异快、多样性高的特点。本研究在国际上首次报道BB冠状病毒S蛋白上的一个重要突变,这个突变使2019-nCoV具有了一个可供Furin蛋白酶切的位点,是除鼠肝炎冠状病毒外所有的其它BB冠状病毒(包括SARS和SARS样(SARS-like)冠状病毒)所不具有的。这个突变有可能增强了2019-nCoV侵染细胞的效率,进而使其传播力显著大于SARS冠状病毒。由于这个突变,2019冠状病毒的包装机制也会不同于SARS等其它大部分Beta冠状病毒,而有可能与鼠肝炎冠状病毒、HIV、埃博拉病毒和一些禽流感病毒的包装机制相同。作为一个意外发现,一些禽流感病毒也可以通过突变获得Furin蛋白酶切位点。对这个重要突变的后续研究将为揭示2019-nCoV传播力强的原因,以及为药物、抗体和疫苗的开发等工作奠定基础。

submitted time 2020-02-14 Hits87983Downloads16645 Comment 0

8. chinaXiv:201812.00002 [pdf]

从来自牛羊的硬蜱中检测到非洲猪瘟病毒的特异性DNA片段

Chen, Ze; Xu, Xiaofeng; Yang, Xiaojun; Dou, Weihao; Jin, Xiufeng; Ji, Haishuo; Liu, Guangyuan ; Luo, Jianxun; Yin, Hong ; Gao, Shan
Subjects: Biology >> Virology

本研究的主要目的是检测硬蜱携带的病毒。作为一个意外发现,检测到一个235 bp的来自非洲猪瘟病毒基因组的特异性片段。随后的测序发现,蜱和羊都具有这个片段,特别是共有一个特异性突变C38T,是目前已发布的非洲猪瘟病毒基因组上对应片段都没有的。

submitted time 2019-01-29 Hits3826Downloads1175 Comment 0

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