Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

Lin, Shanmeng; Lin, Shih‐Chao; Hsu, Jia-Ning; Chang, Chung-ke; Chien, Ching-Ming; Wang, Yongsheng; Wu, Hung-Yi; Jeng, U‐Ser; Kehn-Hall, Kylene; Hou, Ming-Hon

doi:10.1021/acs.jmedchem.9b01913

Cited by 104 publications

(102 citation statements)

References 52 publications

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“…These two sites are shown in Sup. Figure 1E, F. Naproxen stabilized this "non -natural" interface as found in the crystal structure for the designed ligands by Hou et al 13 Figure 1H, E indeed show that naproxen can also bind at this interface in both MERS-CoV and SARS-Cov-2, respectively, but an additional binding site in SARS-CoV-2 monomer was also identified (Sup. Figure 1F).…”

supporting

confidence: 64%

“…Naproxen binding to the Influenza A virus nucleoprotein blocked viral RNA association with the nucleoprotein and impeded its self-association 6,9 ; consequently, naproxen strongly reduced viral transcription/ replication in infected cells and protected mice against an infection with Influenza A virus 6,10 . Viral nucleoproteins are unique to the virus and no equivalent of these proteins are found in the host cell, which makes them attractive targets for potential antivirals [12][13] . Moreover, the viral nucleoprotein is an important diagnostic marker of infection with SARS-COV and /or Influenza A [14][15] .…”

mentioning

confidence: 99%

“…Structure-based modeling of naproxen binding to the nucleoprotein of SARS-CoV-2: The nucleoproteins N of enveloped, positive-sense, single-stranded viruses Coronavirus (CoV) share with negative-sense singlestranded viruses such as Influenza A virus the ability to bind to-and protect genomic viral RNA without sequence specificity and to form self-associated oligomers [12][13][18][19] . Despite the limited sequence similarity between them, the N-terminal domains of three coronaviruses SARS-Cov-1, MERS-CoV, SARS-CoV-2 and Influenza A virus all presented a wide, positively-charged groove in which the viral negatively-charged RNA binds, Figure 1 (A-D) [20][21]13 . The coronavirus N proteins present a central antiparallel sheet of 3-5 β-strands structure and flexible linkers and loops, with emphasis on the large extrusion carrying many basic residues, which likely helps adjust binding to the RNA.…”

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confidence: 99%

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Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

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Dilly

Pizzorno

et al. 2020

Preprint

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There is an urgent need for specific antiviral drugs directed against SARS-CoV-2 both to prevent the most severe forms of COVID-19 and to reduce viral excretion and subsequent virus dissemination; in the present pandemic context, drug repurposing is a priority. Targeting the nucleoprotein N of the SARS-CoV-2 coronavirus in order to inhibit its association with viral RNA could be a strategy to impeding viral replication and possibly other essential functions associated with viral N. The antiviral properties of naproxen, belonging to the NSAID family, previously demonstrated against Influenza A virus, were evaluated against SARS-CoV-2. Naproxen binding to the nucleoprotein of SARS-CoV2 was shown by molecular modeling. In VeroE6 cells and reconstituted human primary respiratory epithelium models of SARS-CoV-2 infection, naproxen inhibited viral replication and protected the bronchial epithelia against SARS-CoV-2 induceddamage. The benefit of naproxen addition to the standard of care is tested in an on-going clinical study.

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confidence: 64%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

Terrier

Dilly

Pizzorno

et al. 2020

Preprint

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“…X‐ray studies were also performed on the identified compounds. Compound 139 blocks MERS‐CoV activity most likely prompting abnormal aggregation of the N protein within the cell . Targeting non‐native PPIs may represent a valuable approach to be possibly extended to SARS‐CoV‐2.…”

Section: Potential Therapeutic Strategies For Sars‐cov‐2mentioning

confidence: 99%

Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

et al. 2020

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The COVID‐19 pandemic caused by SARS‐CoV‐2 infection is spreading at an alarming rate and has created an unprecedented health emergency around the globe. There is no effective vaccine or approved drug treatment against COVID‐19 and other pathogenic coronaviruses. The development of antiviral agents is an urgent priority. Biochemical events critical to the coronavirus replication cycle provided a number of attractive targets for drug development. These include, spike protein for binding to host cell‐surface receptors, proteolytic enzymes that are essential for processing polyproteins into mature viruses, and RNA‐dependent RNA polymerase for RNA replication. There has been a lot of ground work for drug discovery and development against these targets. Also, high‐throughput screening efforts have led to the identification of diverse lead structures, including natural product‐derived molecules. This review highlights past and present drug discovery and medicinal‐chemistry approaches against SARS‐CoV, MERS‐CoV and COVID‐19 targets. The review hopes to stimulate further research and will be a useful guide to the development of effective therapies against COVID‐19 and other pathogenic coronaviruses.

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“…However, the structural and mechanistic basis for newly emerged novel SARS-CoV-2 N protein remain largely unknown. Understanding these aspects should facilitate the discovery of agents that specifically block the coronavirus replication, transcription and viral assembly 30 .…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

Kang

Yang

Hong

et al. 2020

Preprint

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AbstractThe outbreak of coronavirus disease (COVID-19) in China caused by SARS-CoV-2 virus continually lead to worldwide human infections and deaths. It is currently no specific viral protein targeted therapeutics yet. Viral nucleocapsid protein is a potential antiviral drug target, serving multiple critical functions during the viral life cycle. However, the structural information of SARS-CoV-2 nucleocapsid protein is yet to be clear. Herein, we have determined the 2.7 Å crystal structure of the N-terminal RNA binding domain of SARS-CoV-2 nucleocapsid protein. Although overall structure is similar with other reported coronavirus nucleocapsid protein N-terminal domain, the surface electrostatic potential characteristics between them are distinct. Further comparison with mild virus type HCoV-OC43 equivalent domain demonstrates a unique potential RNA binding pocket alongside the β-sheet core. Complemented by in vitro binding studies, our data provide several atomic resolution features of SARS-CoV-2 nucleocapsid protein N-terminal domain, guiding the design of novel antiviral agents specific targeting to SARS-CoV-2.

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Structure-Based Stabilization of Non-native Protein–Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design

Cited by 104 publications

References 52 publications

Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

Broad-spectrum antiviral activity of naproxen: from Influenza A to SARS-CoV-2 Coronavirus

Drug Development and Medicinal Chemistry Efforts toward SARS‐Coronavirus and Covid‐19 Therapeutics

Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites

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