Recent insights into the development of therapeutics against coronavirus diseases by targeting N protein

Chang, Chung-ke; Lo, Shou-Chen; Wang, Yongsheng; Hou, Ming-Hon

doi:10.1016/j.drudis.2015.11.015

Cited by 101 publications

(91 citation statements)

References 103 publications

(129 reference statements)

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“…The N protein of coronaviruses can be divided into two structural domains (NTD and CTD) and three intrinsically disordered regions (the N-arm, central linker region and C-tail) [10,36]. Previous studies demonstrated the involvement of both the structural domains in binding the RNA of SARS-CoV and MHV (either independently or cooperatively as a bipartite) and showed the involvement of the C-terminal domain in oligomerization of the N protein [19,[30][31][32][33][34][36][37][38].…”

Section: Discussionmentioning

confidence: 99%

“…The 5′ two-thirds of the viral genome consists of open reading frames (ORF) 1a and 1b that encode the viral nonstructural proteins (nsps), whereas the 3′ one-third consists of ORFs that encode the viral structural proteins, including the spike (S), membrane (M), envelope (E) and nucleocapsid (N), and accessory proteins. The S, M and E proteins form the viral envelope [7][8][9], whereas the N protein is considered the most important protein that interacts with the viral genomic RNA and packages the RNA into virus particles by recognizing a specific sequence, which is termed the packaging signal [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Nucleocapsid protein-dependent assembly of the RNA packaging signal of Middle East respiratory syndrome coronavirus

Hsin

Chang

et al. 2018

J Biomed Sci

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BackgroundMiddle East respiratory syndrome coronavirus (MERS-CoV) consists of a positive-sense, single-stranded RNA genome and four structural proteins: the spike, envelope, membrane, and nucleocapsid protein. The assembly of the viral genome into virus particles involves viral structural proteins and is believed to be mediated through recognition of specific sequences and RNA structures of the viral genome.Methods and ResultsA culture system for the production of MERS coronavirus-like particles (MERS VLPs) was determined and established by electron microscopy and the detection of coexpressed viral structural proteins. Using the VLP system, a 258-nucleotide RNA fragment, which spans nucleotides 19,712 to 19,969 of the MERS-CoV genome (designated PS258(19712–19969)ME), was identified to function as a packaging signal. Assembly of the RNA packaging signal into MERS VLPs is dependent on the viral nucleocapsid protein. In addition, a 45-nucleotide stable stem-loop substructure of the PS258(19712–19969)ME interacted with both the N-terminal domain and the C-terminal domain of the viral nucleocapsid protein. Furthermore, a functional SARS-CoV RNA packaging signal failed to assemble into the MERS VLPs, which indicated virus-specific assembly of the RNA genome.ConclusionsA MERS-oV RNA packaging signal was identified by the detection of GFP expression following an incubation of MERS VLPs carrying the heterologous mRNA GFP-PS258(19712–19969)ME with virus permissive Huh7 cells. The MERS VLP system could help us in understanding virus infection and morphogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nucleocapsid protein-dependent assembly of the RNA packaging signal of Middle East respiratory syndrome coronavirus

Hsin

Chang

et al. 2018

J Biomed Sci

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“…Human coronavirus, discovered in the 1960s, is known to cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) (423). Many antiviral candidates (e.g., corticosteroids) potentially inhibit human coronavirus, and more details have been elucidated in recent review articles (445)(446)(447).…”

Section: Viruses Targeted By Neither Vaccines Nor Antiviral Drugsmentioning

confidence: 99%

Approved Antiviral Drugs over the Past 50 Years

2016

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SUMMARYSince the first antiviral drug, idoxuridine, was approved in 1963, 90 antiviral drugs categorized into 13 functional groups have been formally approved for the treatment of the following 9 human infectious diseases: (i) HIV infections (protease inhibitors, integrase inhibitors, entry inhibitors, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and acyclic nucleoside phosphonate analogues), (ii) hepatitis B virus (HBV) infections (lamivudine, interferons, nucleoside analogues, and acyclic nucleoside phosphonate analogues), (iii) hepatitis C virus (HCV) infections (ribavirin, interferons, NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors), (iv) herpesvirus infections (5-substituted 2′-deoxyuridine analogues, entry inhibitors, nucleoside analogues, pyrophosphate analogues, and acyclic guanosine analogues), (v) influenza virus infections (ribavirin, matrix 2 protein inhibitors, RNA polymerase inhibitors, and neuraminidase inhibitors), (vi) human cytomegalovirus infections (acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, pyrophosphate analogues, and oligonucleotides), (vii) varicella-zoster virus infections (acyclic guanosine analogues, nucleoside analogues, 5-substituted 2′-deoxyuridine analogues, and antibodies), (viii) respiratory syncytial virus infections (ribavirin and antibodies), and (ix) external anogenital warts caused by human papillomavirus infections (imiquimod, sinecatechins, and podofilox). Here, we present for the first time a comprehensive overview of antiviral drugs approved over the past 50 years, shedding light on the development of effective antiviral treatments against current and emerging infectious diseases worldwide.

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“…Whether this cross-interaction has beneficial or detrimental effects on viral replication has never been explored. Investigation of the interaction between CoV N proteins could lead to insights into virus evolution, anti-CoV drug development and vaccine design (Chang et al, 2016;Lo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Nucleocapsid proteins from other swine enteric coronaviruses differentially modulate PEDV replication

2020

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A B S T R A C TPorcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV) and porcine deltacoronavirus (PDCoV) share tropism for swine intestinal epithelial cells. Whether mixing of viral components during co-infection alters pathogenic outcomes or viral replication is not known. In this study, we investigated how different coronavirus nucleocapsid (CoV N) proteins interact and affect PEDV replication. We found that PDCoV N and TGEV N can competitively interact with PEDV N. However, the presence of PDCoV or TGEV N led to very different outcomes on PEDV replication. While PDCoV N significantly suppresses PEDV replication, overexpression of TGEV N, like that of PEDV N, increases production of PEDV RNA and virions. Despite partial interchangeability in nucleocapsid oligomerization and viral RNA synthesis, endogenous PEDV N cannot be replaced in the production of infectious PEDV particles. Results from this study give insights into functional compatibilities and evolutionary relationship between CoV viral proteins during viral co-infection and co-evolution.

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Recent insights into the development of therapeutics against coronavirus diseases by targeting N protein

Cited by 101 publications

References 103 publications

Nucleocapsid protein-dependent assembly of the RNA packaging signal of Middle East respiratory syndrome coronavirus

Nucleocapsid protein-dependent assembly of the RNA packaging signal of Middle East respiratory syndrome coronavirus

Approved Antiviral Drugs over the Past 50 Years

Nucleocapsid proteins from other swine enteric coronaviruses differentially modulate PEDV replication

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