共查询到20条相似文献,搜索用时 31 毫秒
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《Saudi Journal of Biological Sciences》2022,29(5):3456-3465
The inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) and papain-like protease (PLpro) prevents viral multiplications; these viral enzymes have been recognized as one of the most favorable targets for drug discovery against SARS-CoV-2. In the present study, we screened 225 phytocompounds present in 28 different Indian spices to identify compounds as potential inhibitors of SARS-CoV-2 Mpro and PLpro. Molecular docking, molecular dynamics simulation, molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energy calculations, and absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were done. Based on binding affinity, dynamics behavior, and binding free energies, the present study identifies pentaoxahexacyclo-dotriacontanonaen-trihydroxybenzoate derivative (PDT), rutin, and dihyroxy-oxan-phenyl-chromen-4-one derivative (DOC), luteolin-7-glucoside-4′-neohesperidoside as promising inhibitors of SARS-CoV-2 Mpro and PLpro, respectively. 相似文献
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目前新型冠状病毒(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)感染所致的新型冠状病毒肺炎(corona virus disease, COVID-19)已成为威胁人类健康和安全的全球性流行性疾病。随着新突变株的不断出现,寻找有效治疗药物和靶点迫在眉睫。干扰素刺激基因(interferon-stimulated genes, ISGs)是由干扰素(interferons, IFNs)诱导后表达上调的一类基因,在宿主抵抗病毒感染过程中发挥着至关重要的作用。研究表明,ISGs能够靶向许多病毒复制的不同阶段发挥抗病毒作用,然而SARS-CoV-2也进化出各种策略干扰或逃避宿主天然免疫。因此,全面了解SARS-CoV-2与ISGs相互作用,对于设计抗病毒策略至关重要。本文简要综述不同ISGs抵抗SARS-CoV-2的作用机制,为开发新型的抗病毒药物提供思路和理论依据。 相似文献
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Marimuthu Ragavan Rameshkumar Purushothaman Indu Narasingam Arunagirinathan Babu Venkatadri Hamed A. El-Serehy Ajaz Ahmad 《Saudi Journal of Biological Sciences》2021,28(1):448-458
An outbreak of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been recognized as a global health concern. Since, no specific antiviral drug is proven effective for treatment against COVID-19, identification of new therapeutics is an urgent need. In this study, flavonoid compounds were analyzed for its inhibitory potential against important protein targets of SARS-CoV-2 using computational approaches. Virtual docking was performed for screening of flavonoid compounds retrieved from PubChem against the main protease of SARS-CoV-2 using COVID-19 docking server. The cut off of dock score was set to >?9 kcal/mol and screened compounds were individually docked against main protease, RNA-dependent RNA polymerase, and spike proteins using AutoDock 4.1 software. Finally, lead flavonoid compounds were subjected to ADMET analysis. A total of 458 flavonoid compounds were virtually screened against main protease target and 36 compounds were selected based on the interaction energy value >?9 kcal/mol. Furthermore, these compounds were individually docked against protein targets and top 10 lead compounds were identified. Among the lead compounds, agathisflavone showed highest binding energy value of ?8.4 kcal/mol against main protease, Albireodelphin showed highest dock score of ?9.8 kcal/mol and ?11.2 kcal/mol against RdRp, and spike proteins, respectively. Based on the high dock score and ADMET properties, top 5 lead molecules such as Albireodelphin, Apigenin 7-(6″-malonylglucoside), Cyanidin-3-(p-coumaroyl)-rutinoside-5-glucoside, Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside) and (-)-Maackiain-3-O-glucosyl-6″-O-malonate were identified as potent inhibitors against main protease, RdRp, and spike protein targets of SARS-CoV-2. These all compounds are having non-carcinogenic and non-mutagenic properties. This study finding suggests that the screened compounds include Albireodelphin, Apigenin 7-(6″-malonylglucoside), Cyanidin-3-(p-coumaroyl)-rutinoside-5-glucoside, Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside) and (-)-Maackiain-3-O-glucosyl-6″-O-malonate could be the potent inhibitors of SARS-CoV-2 targets. 相似文献
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Terrence Tsz-Tai Yuen Jasper Fuk-Woo Chan Bingpeng Yan Cynthia Cheuk-Ying Shum Yuanchen Liu Huiping Shuai Yuxin Hou Xiner Huang Bingjie Hu Yue Chai Chaemin Yoon Tianrenzheng Zhu Huan Liu Jialu Shi Jinjin Zhang Jian-Piao Cai Anna Jinxia Zhang Jie Zhou Feifei Yin Shuofeng Yuan Bao-Zhong Zhang Hin Chu 《International journal of biological sciences》2022,18(12):4714
The Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the biggest public health challenge the world has witnessed in the past decades. SARS-CoV-2 undergoes constant mutations and new variants of concerns (VOCs) with altered transmissibility, virulence, and/or susceptibility to vaccines and therapeutics continue to emerge. Detailed analysis of host factors involved in virus replication may help to identify novel treatment targets. In this study, we dissected the metabolome derived from COVID-19 patients to identify key host factors that are required for efficient SARS-CoV-2 replication. Through a series of metabolomic analyses, in vitro, and in vivo investigations, we identified ATP citrate lyase (ACLY) as a novel host factor required for efficient replication of SARS-CoV-2 wild-type and variants, including Omicron. ACLY should be further explored as a novel intervention target for COVID-19. 相似文献
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Ziwei Chen Pinglang Ruan Lili Wang Xinmin Nie Xuejun Ma Yurong Tan 《Journal of cellular and molecular medicine》2021,25(2):1274-1289
COVID-19 caused by SARS-CoV-2 is pandemic with a severe morbidity and mortality rate across the world. Despite the race for effective vaccine and drug against further expansion and fatality rate of this novel coronavirus, there is still lack of effective antiviral therapy. To this effect, we deemed it necessary to identify potential B and T cell epitopes from the envelope S protein. This can be used as potential targets to develop anti-SARS-CoV-2 vaccine preparations. In this study, we used immunoinformatics to identify conservative B and T cell epitopes for S proteins of SARS-CoV-2, which might play roles in the initiation of SARS-CoV-2 infection. We identified the B cell and T cell peptide epitopes of S protein and their antigenicity, as well as the interaction between the peptide epitopes and human leucocyte antigen (HLA). Among the B cell epitopes, ‘EILDITPCSFGGVS’ has the highest score of antigenicity and great immunogenicity. In T cell epitopes, MHC-I peptide ‘KIADYNYKL’ and MHC-II peptide ‘LEILDITPC’ were identified as high antigens. Besides, docking analysis showed that the predicted peptide ‘KIADYNYKL’ was closely bound to the HLA-A*0201. The results of molecular dynamics simulation through GROMACS software showed that ‘HLA-A*0201~peptide’ complex was very stable. And the peptide we selected could induce the T cell response similar to that of SARS-CoV-2 infection. Moreover, the predicted peptides were highly conserved in different isolates from different countries. The antigenic epitopes presumed in this study were effective new vaccine targets to prevent SARS-CoV-2 infection. 相似文献
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Man Wang Wenguang Chang Lei Zhang Yuan Zhang 《International journal of biological sciences》2022,18(15):5827
The rapid dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a global public health emergency. The host immune response to SARS-CoV-2 plays a key role in COVID-19 pathogenesis. SARS-CoV-2 can induce aberrant and excessive immune responses, leading to cytokine storm syndrome, autoimmunity, lymphopenia, neutrophilia and dysfunction of monocytes and macrophages. Pyroptosis, a proinflammatory form of programmed cell death, acts as a host defense mechanism against infections. Pyroptosis deprives the replicative niche of SARS-CoV-2 by inducing the lysis of infected cells and exposing the virus to extracellular immune attack. Notably, SARS-CoV-2 has evolved sophisticated mechanisms to hijack this cell death mode for its own survival, propagation and shedding. SARS-CoV-2-encoded viral products act to modulate various key components in the pyroptosis pathways, including inflammasomes, caspases and gasdermins. SARS-CoV-2-induced pyroptosis contriubtes to the development of COVID-19-associated immunopathologies through leakage of intracellular contents, disruption of immune system homeostasis or exacerbation of inflammation. Therefore, pyroptosis has emerged as an important mechanism involved in COVID-19 immunopathogenesis. However, the entangled links between pyroptosis and SARS-CoV-2 pathogenesis lack systematic clarification. In this review, we briefly summarize the characteristics of SARS-CoV-2 and COVID-19-related immunopathologies. Moreover, we present an overview of the interplay between SARS-CoV-2 infection and pyroptosis and highlight recent research advances in the understanding of the mechanisms responsible for the implication of the pyroptosis pathways in COVID-19 pathogenesis, which will provide informative inspirations and new directions for further investigation and clinical practice. Finally, we discuss the potential value of pyroptosis as a therapeutic target in COVID-19. An in-depth discussion of the underlying mechanisms of COVID-19 pathogenesis will be conducive to the identification of potential therapeutic targets and the exploration of effective treatment measures aimed at conquering SARS-CoV-2-induced COVID-19. 相似文献
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Fang Sun Chenglin Mu Hang Fai Kwok Jiyuan Xu Yingliang Wu Wanhong Liu Jean-Marc Sabatier Cdric Annweiler Xugang Li Zhijian Cao Yingqiu Xie 《International journal of biological sciences》2021,17(9):2348
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to more than 150 million infections and about 3.1 million deaths up to date. Currently, drugs screened are urgently aiming to block the infection of SARS-CoV-2. Here, we explored the interaction networks of kinase and COVID-19 crosstalk, and identified phosphoinositide 3-kinase (PI3K)/AKT pathway as the most important kinase signal pathway involving COVID-19. Further, we found a PI3K/AKT signal pathway inhibitor capivasertib restricted the entry of SARS-CoV-2 into cells under non-cytotoxic concentrations. Lastly, the signal axis PI3K/AKT/FYVE finger-containing phosphoinositide kinase (PIKfyve)/PtdIns(3,5)P2 was revealed to play a key role during the cellular entry of viruses including SARS-CoV-2, possibly providing potential antiviral targets. Altogether, our study suggests that the PI3K/AKT kinase inhibitor drugs may be a promising anti-SARS-CoV-2 strategy for clinical application, especially for managing cancer patients with COVID-19 in the pandemic era. 相似文献
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Suelen Silva Gomes Dias Vinicius Cardoso Soares Andr C. Ferreira Carolina Q. Sacramento Natalia Fintelman-Rodrigues Jairo R. Temerozo Lívia Teixeira Marcos Alexandre Nunes da Silva Ester Barreto Mayara Mattos Caroline S. de Freitas Isaclaudia G. Azevedo-Quintanilha Pedro Paulo A. Manso Milene D. Miranda Marilda Mendona Siqueira Eugenio D. Hottz Camila R. R. Po Dumith C. Bou-Habib Debora F. Barreto-Vieira Fernando A. Bozza Thiago M. L. Souza Patricia T. Bozza 《PLoS pathogens》2020,16(12)
Viruses are obligate intracellular parasites that make use of the host metabolic machineries to meet their biosynthetic needs. Thus, identifying the host pathways essential for the virus replication may lead to potential targets for therapeutic intervention. The mechanisms and pathways explored by SARS-CoV-2 to support its replication within host cells are not fully known. Lipid droplets (LD) are organelles with major functions in lipid metabolism, energy homeostasis and intracellular transport, and have multiple roles in infections and inflammation. Here we described that monocytes from COVID-19 patients have an increased LD accumulation compared to SARS-CoV-2 negative donors. In vitro, SARS-CoV-2 infection were seen to modulate pathways of lipid synthesis and uptake as monitored by testing for CD36, SREBP-1, PPARγ, and DGAT-1 expression in monocytes and triggered LD formation in different human cell lines. LDs were found in close apposition with SARS-CoV-2 proteins and double-stranded (ds)-RNA in infected Vero cells. Electron microscopy (EM) analysis of SARS-CoV-2 infected Vero cells show viral particles colocalizing with LDs, suggestive that LDs might serve as an assembly platform. Pharmacological modulation of LD formation by inhibition of DGAT-1 with A922500 significantly inhibited SARS-CoV-2 replication as well as reduced production of mediators pro-inflammatory response. Taken together, we demonstrate the essential role of lipid metabolic reprograming and LD formation in SARS-CoV-2 replication and pathogenesis, opening new opportunities for therapeutic strategies to COVID-19. 相似文献
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Monika Radvánszka Evan D. Paul Roman Hajdu Kristína Boršová Viera Kováčová Piotr Putaj Stanislava Bírová Ivana Čirková Martin Čarnecký Katarína Buranovská Adrián Szobi Nina Vojtaššáková Diana Drobná Viktória Čabanová Monika Sláviková Martina Ličková Veronika Vaňová Sabína Fumačová Havlíková Ľubomíra Lukáčiková Ivana Kajanová Juraj Koči Diana Rusňáková Tatiana Sedláčková Klaas E. A. Max Thomas Tuschl Tomáš Szemes Boris Klempa Pavol Čekan 《Microbial biotechnology》2022,15(7):1995-2021
Sensitive and accurate RT-qPCR tests are the primary diagnostic tools to identify SARS-CoV-2-infected patients. While many SARS-CoV-2 RT-qPCR tests are available, there are significant differences in test sensitivity, workflow (e.g. hands-on-time), gene targets and other functionalities that users must consider. Several publicly available protocols shared by reference labs and public health authorities provide useful tools for SARS-CoV-2 diagnosis, but many have shortcomings related to sensitivity and laborious workflows. Here, we describe a series of SARS-CoV-2 RT-qPCR tests that are originally based on the protocol targeting regions of the RNA-dependent RNA polymerase (RdRp) and envelope (E) coding genes developed by the Charité Berlin. We redesigned the primers/probes, utilized locked nucleic acid nucleotides, incorporated dual probe technology and conducted extensive optimizations of reaction conditions to enhance the sensitivity and specificity of these tests. By incorporating an RNase P internal control and developing multiplexed assays for distinguishing SARS-CoV-2 and influenza A and B, we streamlined the workflow to provide quicker results and reduced consumable costs. Some of these tests use modified enzymes enabling the formulation of a room temperature-stable master mix and lyophilized positive control, thus increasing the functionality of the test and eliminating cold chain shipping and storage. Moreover, a rapid, RNA extraction-free version enables high sensitivity detection of SARS-CoV-2 in about an hour using minimally invasive, self-collected gargle samples. These RT-qPCR assays can easily be implemented in any diagnostic laboratory and can provide a powerful tool to detect SARS-CoV-2 and the most common seasonal influenzas during the vaccination phase of the pandemic. 相似文献
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为确定治疗新型冠状病毒(SARS-CoV-2)感染的候选药物,开展了针对SARS-CoV-2的药物虚拟筛选研究。以SARS-CoV-2的刺突蛋白(S蛋白)和3CL蛋白酶(主蛋白酶)作为药物靶点,以美国食品药品监督管理局(FDA)批准上市的2 726个小分子药物作为候选,通过分子对接方法,筛选出了3种(阿巴瑞克(Abarelix)、西曲瑞克(Cetrorelix)、鞣酸(Tannic acid))与S蛋白具有较强结合能力的小分子药物,1种(戈舍瑞林(Goserelin))与3CL蛋白酶具有较好结合能力的小分子药物,它们理论上都具有抑制新型冠状病毒复制的效果。将靶向3CL蛋白酶的候选药物与辉瑞公司开发的药物Paxlovid进行比较,发现其作用位点均集中于3CL蛋白酶的第130-200位的残基周围,具有相似的结合位点与相互作用。此外也对候选药物的物理与化学性质及与基因相互作用进行了分析。本研究可为开发新型冠状病毒感染的治疗药物提供参考。 相似文献
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Du Jiao Xiaorui Dong Yingyan Yu Chaochun Wei 《International journal of biological sciences》2021,17(14):3717
SARS-CoV-2 belongs to the coronavirus family. Comparing genomic features of viral genomes of coronavirus family can improve our understanding about SARS-CoV-2. Here we present the first pan-genome analysis of 3,932 whole genomes of 101 species out of 4 genera from the coronavirus family. We found that a total of 181 genes in the pan-genome of coronavirus family, among which only 3 genes, the S gene, M gene and N gene, are highly conserved. We also constructed a pan-genome from 23,539 whole genomes of SARS-CoV-2. There are 13 genes in total in the SARS-CoV-2 pan-genome. All of the 13 genes are core genes for SARS-CoV-2. The pan-genome of coronaviruses shows a lower level of diversity than the pan-genomes of other RNA viruses, which contain no core gene. The three highly conserved genes in coronavirus family, which are also core genes in SARS-CoV-2 pan-genome, could be potential targets in developing nucleic acid diagnostic reagents with a decreased possibility of cross-reaction with other coronavirus species. 相似文献
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Nicholas C. Wu Meng Yuan Sandhya Bangaru Deli Huang Xueyong Zhu Chang-Chun D. Lee Hannah L. Turner Linghang Peng Linlin Yang Dennis R. Burton David Nemazee Andrew B. Ward Ian A. Wilson 《PLoS pathogens》2020,16(12)
Epitopes that are conserved among SARS-like coronaviruses are attractive targets for design of cross-reactive vaccines and therapeutics. CR3022 is a SARS-CoV neutralizing antibody to a highly conserved epitope on the receptor binding domain (RBD) on the spike protein that is able to cross-react with SARS-CoV-2, but with lower affinity. Using x-ray crystallography, mutagenesis, and binding experiments, we illustrate that of four amino acid differences in the CR3022 epitope between SARS-CoV-2 and SARS-CoV, a single mutation P384A fully determines the affinity difference. CR3022 does not neutralize SARS-CoV-2, but the increased affinity to SARS-CoV-2 P384A mutant now enables neutralization with a similar potency to SARS-CoV. We further investigated CR3022 interaction with the SARS-CoV spike protein by negative-stain EM and cryo-EM. Three CR3022 Fabs bind per trimer with the RBD observed in different up-conformations due to considerable flexibility of the RBD. In one of these conformations, quaternary interactions are made by CR3022 to the N-terminal domain (NTD) of an adjacent subunit. Overall, this study provides insights into antigenic variation and potential cross-neutralizing epitopes on SARS-like viruses. 相似文献
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Zhengrong Zhang You Zheng Zubiao Niu Bo Zhang Chenxi Wang Xiaohong Yao Haoran Peng Del Nonno Franca Yunyun Wang Yichao Zhu Yan Su Meng Tang Xiaoyi Jiang He Ren Meifang He Yuqi Wang Lihua Gao Ping Zhao Hanping Shi Zhaolie Chen Xiaoning Wang Mauro Piacentini Xiuwu Bian Gerry Melino Liang Liu Hongyan Huang Qiang Sun 《Cell death and differentiation》2021,28(9):2765
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (~45.1 nm/s) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.Subject terms: Cell biology, Molecular biology 相似文献
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Virologica Sinica - SARS-CoV-2 has become a global pandemic threatening human health and safety. It is urgent to find effective therapeutic agents and targets with the continuous emergence of novel... 相似文献
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Jordan M. Meyers Muthukumar Ramanathan Ronald L. Shanderson Aimee Beck Laura Donohue Ian Ferguson Margaret G. Guo Deepti S. Rao Weili Miao David Reynolds Xue Yang Yang Zhao Yen-Yu Yang Catherine Blish Yinsheng Wang Paul A. Khavari 《PLoS pathogens》2021,17(10)
Viral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 severity, including the TRIM4 interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was associated with inhibited host protein translation whereas ORF6 localization with MAVS was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 protease, with specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2. 相似文献