The recent outbreak of COVID-19 has created a serious health crisis with fatFal infectious viral diseases, such as Severe Acute Respiratory Syndrome (SARS). The nsp13, a helicase of coronaviruses is an essential element for viral replication that unwinds secondary structures of DNA and RNA, and is thus considered a major therapeutic target for treatment. The replication of coronaviruses and other retroviruses occurs in the cytoplasm of infected cells, in association with viral replication organelles, called virus-induced cytosolic double-membrane vesicles (DMVs). In addition, an increase in cytosolic Ca²⁺ concentration accelerates viral replication. However, the molecular mechanism of nsp13 in the presence of Ca²⁺ is not well understood. In this study, we applied biochemical methods and single-molecule techniques to demonstrate how nsp13 achieves its unwinding activity while performing ATP hydrolysis in the presence of Ca²⁺. Our study found that nsp13 could efficiently unwind double stranded (ds) DNA under physiological concentration of Ca²⁺ of cytosolic DMVs. These findings provide new insights into the properties of nsp13 in the range of calcium in cytosolic DMVs.

09 Jul 2019·Nucleic Acids ResearchQ2 · BIOLOGY

Delicate structural coordination of the Severe Acute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis

Q2 · BIOLOGY

ArticleOA

Author: Zheng, Litao ; Zhang, Lianqi ; Wang, Jin ; Yan, Liming ; Jia, Zhihui ; Ren, Zhilin ; Wu, Lijie ; Rao, Zihe ; Ming, Zhenhua ; Lou, Zhiyong ; Guo, Jing

AbstractTo date, an effective therapeutic treatment that confers strong attenuation toward coronaviruses (CoVs) remains elusive. Of all the potential drug targets, the helicase of CoVs is considered to be one of the most important. Here, we first present the structure of the full-length Nsp13 helicase of SARS-CoV (SARS-Nsp13) and investigate the structural coordination of its five domains and how these contribute to its translocation and unwinding activity. A translocation model is proposed for the Upf1-like helicase members according to three different structural conditions in solution characterized through H/D exchange assay, including substrate state (SARS-Nsp13-dsDNA bound with AMPPNP), transition state (bound with ADP-AlF4−) and product state (bound with ADP). We observed that the β19–β20 loop on the 1A domain is involved in unwinding process directly. Furthermore, we have shown that the RNA dependent RNA polymerase (RdRp), SARS-Nsp12, can enhance the helicase activity of SARS-Nsp13 through interacting with it directly. The interacting regions were identified and can be considered common across CoVs, which provides new insights into the Replication and Transcription Complex (RTC) of CoVs.

01 Aug 2014·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Evaluation of SSYA10-001 as a Replication Inhibitor of Severe Acute Respiratory Syndrome, Mouse Hepatitis, and Middle East Respiratory Syndrome Coronaviruses

Q2 · MEDICINE

Article

Author: Elliott, Ruth ; Adedeji, Adeyemi O. ; Coleman, Christopher M. ; Frieman, Matthew B. ; Kassim, Ademola ; Singh, Kamalendra ; Weiss, Susan R. ; Sarafianos, Stefan G.

ABSTRACTWe have previously shown that SSYA10-001 blocks severe acute respiratory syndrome coronavirus (SARS-CoV) replication by inhibiting SARS-CoV helicase (nsp13). Here, we show that SSYA10-001 also inhibits replication of two other coronaviruses, mouse hepatitis virus (MHV) and Middle Eastern respiratory syndrome coronavirus (MERS-CoV). A putative binding pocket for SSYA10-001 was identified and shown to be similar in SARS-CoV, MERS-CoV, and MHV helicases. These studies show that it is possible to target multiple coronaviruses through broad-spectrum inhibitors.

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SARS-CoV-1 Nsp13

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