Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification.
Characterization of the SARS-CoV-2 ExoN (nsp14ExoN-nsp10) complex: implications for its role in viral genome stability and inhibitor identification.
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DOI：
10.1093/nar/gkab1303
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发表时间：
2022-02-22
影响因子：
14.9
通讯作者：
McHugh PJ
中科院分区：
文献类型：
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作者：
Baddock HT;Brolih S;Yosaatmadja Y;Ratnaweera M;Bielinski M;Swift LP;Cruz-Migoni A;Fan H;Keown JR;Walker AP;Morris GM;Grimes JM;Fodor E;Schofield CJ;Gileadi O;McHugh PJ
SARS-CoV-2冠状病毒是目前全球大流行的病原体。SARS-CoV-2属于巢病毒目，具有非常大的RNA基因组。有人提出，冠状病毒（CoV）基因组复制的保真度是由RNA核酸酶复合物，包括非结构蛋白14和10（nsp 14-nsp 10），一个有吸引力的抗病毒抑制的目标帮助。我们的研究结果验证了SARS-CoV-2 nsp 14-nsp 10复合物具有RNase活性的报道。详细的功能表征表明nsp 14-nsp 10是一种多功能核酸酶，能够消化各种RNA结构，包括具有封闭3′-末端的RNA结构。与在复制过程中维持病毒基因组完整性的作用一致，我们发现nsp 14-nsp 10活性通过由nsp 12-nsp 7-nsp 8（nsp 12 -7-8）组成的病毒RNA依赖性RNA聚合酶复合物（RdRp）增强，并证明这种刺激是由nsp 8介导的。我们提出，nsp 14-nsp 10在维持复制保真度的作用超越了经典的校对清除新生的复制RNA链的一系列潜在的复制终止畸变。使用我们开发的检测方法，我们鉴定了抑制nsp 14-nsp 10的药物和药物样分子，包括已知的SARS-CoV-2主要蛋白酶（Mpro）抑制剂ebselen和HIV整合酶抑制剂raltegravir，揭示了COVID-19治疗中多功能抑制剂的潜力。
The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14–nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14–nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14–nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3′-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14–nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12–nsp7–nsp8 (nsp12–7–8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14–nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14–nsp10, including the known SARS-CoV-2 major protease (Mpro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.
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影响因子：
14.8
作者：
Exell JC;Thompson MJ;Finger LD;Shaw SJ;Debreczeni J;Ward TA;McWhirter C;Siöberg CL;Martinez Molina D;Abbott WM;Jones CD;Nissink JW;Durant ST;Grasby JA
通讯作者：
Grasby JA
影响因子：
5
作者：
Imbert I;Snijder EJ;Dimitrova M;Guillemot JC;Lécine P;Canard B
通讯作者：
Canard B
影响因子：
56.9
作者：
Liu, Chang;Shi, Wei;Becker, Scott T.;Schatz, David G.;Liu, Bin;Yang, Yang
通讯作者：
Yang, Yang
影响因子：
2.7
作者：
Chapman, Timothy M.;Wallace, Claire;Saxty, Barbara
通讯作者：
Saxty, Barbara
DOI：
10.1039/d0cc06870e
发表时间：
2021-02-15
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Malla TR;Tumber A;John T;Brewitz L;Strain-Damerell C;Owen CD;Lukacik P;Chan HTH;Maheswaran P;Salah E;Duarte F;Yang H;Rao Z;Walsh MA;Schofield CJ
通讯作者：
Schofield CJ