Structure of RNA-Dependent RNA Polymerase - a Major Antiviral Drug Target of 2019-nCoV

ON2020-03-20TAG: ShanghaiTech UniversityCATEGORY: SIAIS


Recently, a joint research team led by Rao Zihe, Distinguished Adjunct Professor at SIAIS (Shanghai Institute for Advanced Immunochemical Studies), ShanghaiTech University, Wang Quan, Assistant Professor at School of Life Science and Technology (SLST) and SIAIS, ShanghaiTech University and Lou Zhiyong, Associate Professor at Tsinghua University, reported a 2.9 ? cryo-EM structure of the RNA-dependent RNA polymerase of 2019-nCoV with cofactors, which is a major antiviral drug target and a primary target for an antiviral drug, remdesivir.

Coronavirus disease 2019 (COVID-19), caused by 2019-nCoV, is spreading rapidly across the world and has been announced as a “global pandemic” by the World Health Organization (WHO) on 15 March 2020. According to the WHO, there are over 200,000 confirmed cases and more than 8,600 deaths in 166 countries, areas or territories (last updated by WHO on 18 March 2020 18:00 CET, https://experience.arcgis.com/experience/685d0ace521648f8a5beee

ee1b9125cd). 


The 2019-nCoV is a new member of the betacoronavirus genus and closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). A 2019-nCoV infection generally causes flu-like symptoms, such as fever, dry cough and fatigue. Severe cases may progress to multi-organ failure and even death. Unfortunately, there is no vaccine or specific medicine to prevent or treat COVID-19 at present. Nonetheless, an antiviral drug candidate named remdesivir (development code GS-5734), originally developed for treating the Ebola patients, was considered as one of the most promising candidates based on its broad antiviral spectrum (https://apps.who.int/iris/bitstream/handle/10665/330680/WHO-HEO-RDBlueprint%28nCoV

%29-2020.1-eng.pdf?ua=1).


Coronaviruses employ a multi-subunit replication/transcription machinery, comprising of a set of non-structural proteins (nsp) produced as cleavage products of the ORF1a and ORF1ab viral polyproteins to facilitate virus replication and transcription. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and a primary target for the antiviral drug, remdesivir. Due to the crucial function of nsp12, the characterization of its structure in complex with its cofactors nsp7 and nsp8 provides atomic-level information to facilitate rational antiviral drug design and development.

The joint research team led by Professors Rao Zihe, Wang Quan, and Lou Zhiyong, reports the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8, at a resolution of 2.9 ?. Besides the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 also possesses a newly identified β-hairpin domain at its N-terminal, where key residues for viral replication and transcription are observed. A comparative analysis showing how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp.

During the COVID-19 pandemic, ShanghaiTech University has provided tremendous efforts to the joint research team. The strong support from research facilities, campus services, laboratory supplies and healthcare services, ensured a safe and supportive environment for the joint research team to successfully carry out this challenging project and attain satisfactory achievements.

 

On March 17th 2020, this research work was published on bioRxiv website, entitled “Structure of RNA-dependent RNA polymerase from 2019-nCoV, a major antiviral drug target” (https://www.biorxiv.org/content/10.1101/2020.03.16

.993386v1doi:10.1101/2020.03.16.993386).


To assist more researchers with their work on COVID-19, especially in the drug discovery field, data of this cryo-EM structure has been submitted to the Protein Data Bank (PDB), and can be downloaded via PDB ID 6M71. As the cryo-EM structure are still being processed by PDB/EMDB, please contact Dr. Yang Xiuna (Research Associate Professor of SIAIS) at yangxn@shanghaitech.edu.cn for urgent requests of this structure.