Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir.
Wanchao Yin,Wanchao Yin,Chunyou Mao,Xiaodong Luan,Xiaodong Luan,Dan-Dan Shen,Qingya Shen,Haixia Su,Xiaoxi Wang,Fulai Zhou,Wenfeng Zhao,Minqi Gao,Shenghai Chang,Yuan Chao Xie,Guanghui Tian,He wei Jiang,Sheng-Ce Tao,Jingshan Shen,Yi Jiang,Hualiang Jiang,Yechun Xu,Shuyang Zhang,Yan Zhang,H. Eric Xu +23 more
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Cryo–electron microscopy structures of the SARS-CoV-2 RdRp provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.Abstract:
The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.read more
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Coronavirus biology and replication: implications for SARS-CoV-2.
TL;DR: The first discoveries that shape the current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle are summarized and relate that to the knowledge of coronavirus biology.
Journal ArticleDOI
COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives.
TL;DR: The interaction between the viral spike protein and angiotensin-converting enzyme 2, which triggers entry of the virus into host cells, is likely to be involved in the cardiovascular manifestations of COVID-19.
Journal ArticleDOI
SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.
Flávio P. Veras,Marjorie Cornejo Pontelli,Camila Meirelles de Souza Silva,Juliana E Toller-Kawahisa,Mikhael de Lima,Daniele C. Nascimento,Ayda Henriques Schneider,Diego B. Caetite,Lucas Alves Tavares,Isadora Marques Paiva,Roberta Ribeiro Costa Rosales,David F. Colón,Ronaldo B. Martins,Italo A. Castro,Glaucia M. Almeida,Maria Isabel Fernandes Lopes,Maira N. Benatti,Letícia Pastorelli Bonjorno,Marcela C Giannini,Rodrigo Luppino-Assad,Sérgio C. L. Almeida,Fernando Crivelenti Vilar,Rodrigo de Carvalho Santana,Valdes Roberto Bollela,Maria Auxiliadora-Martins,Marcos C. Borges,Carlos Henrique Miranda,Antonio Pazin-Filho,Luis Lamberti Pinto da Silva,Larissa D. Cunha,Dario S. Zamboni,Felipe Dal-Pizzol,Luiz O. Leiria,Li Siyuan,Sabrina Setembre Batah,Alexandre Todorovic Fabro,Thais Mauad,Marisa Dolhnikoff,Amaro Nunes Duarte-Neto,Paulo Hilário Nascimento Saldiva,Thiago M. Cunha,José C. Alves-Filho,Eurico Arruda,Paulo Louzada-Junior,Renê Donizeti Ribeiro de Oliveira,Fernando Q. Cunha +45 more
TL;DR: It is described that SARS-CoV-2 triggers the release of ACE2-depended neutrophil extracellular traps (NETs) that mediate lung pathology, supporting the use of NETs inhibitors for COVID-19 treatment.
Journal ArticleDOI
Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.
Quan Wang,Jiqin Wu,Haofeng Wang,Haofeng Wang,Yan Gao,Qiaojie Liu,An Mu,An Mu,Wenxin Ji,Wenxin Ji,Liming Yan,Yan Zhu,Chen Zhu,Xiang Fang,Xiaobao Yang,Yucen Huang,H. Gao,H. Gao,Fengjiang Liu,Ji Ge,Qianqian Sun,Xiuna Yang,Wenqing Xu,Zhi-Jie Liu,Haitao Yang,Zhiyong Lou,Biao Jiang,Luke W. Guddat,Peng Gong,Zihe Rao,Zihe Rao,Zihe Rao +31 more
TL;DR: The molecular basis of SARS-CoV-2 RNA replication is examined by determining the cryo-EM structures of the stalled pre-/post- translocated polymerase complexes and the inhibition mechanisms of the triphosphate metabolite of remdesivir are investigated through structural and kinetic analyses.
Journal ArticleDOI
Structure of replicating SARS-CoV-2 polymerase.
Hauke S. Hillen,Goran Kokic,Lucas Farnung,Christian Dienemann,Dimitry Tegunov,Patrick Cramer +5 more
TL;DR: A cryo-electron microscopy structure of the RNA-dependent RNA polymerase of SARS-CoV-2 sheds light on coronavirus replication and enables the analysis of the inhibitory mechanisms of candidate antiviral drugs.
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