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Article ; Online: A Cool Look at Positive-Strand RNA Virus Replication Organelles: New Insights from Cryo-Electron Microscopy.

de Beijer, Nina L / Snijder, Eric J / Bárcena, Montserrat

2024

Abstract: Positive-strand RNA viruses encompass a variety of established and emerging eukaryotic pathogens. Their genome replication is confined to specialized cytoplasmic membrane compartments known as replication organelles (ROs). These ROs derive from host ... ...

Abstract	Positive-strand RNA viruses encompass a variety of established and emerging eukaryotic pathogens. Their genome replication is confined to specialized cytoplasmic membrane compartments known as replication organelles (ROs). These ROs derive from host membranes, transformed into distinct structures such as invaginated spherules or intricate membrane networks including single- and/or double-membrane vesicles. ROs play a vital role in orchestrating viral RNA synthesis and evading detection by innate immune sensors of the host. In recent years, groundbreaking cryo-electron microscopy studies conducted with several prototypic viruses have significantly advanced our understanding of RO structure and function. Notably, these studies unveiled the presence of crown-shaped multimeric viral protein complexes that seem to actively participate in viral RNA synthesis and regulate the release of newly synthesized RNA into the cytosol for translation and packaging. These findings have shed light on novel viral functions and fascinating macromolecular complexes that delineate promising new avenues for future research.
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev-biochem-052521-115736
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Article ; Online: The Main Protease of Middle East Respiratory Syndrome Coronavirus Induces Cleavage of Mitochondrial Antiviral Signaling Protein to Antagonize the Innate Immune Response.

van Huizen, Mariska / Vendrell, Xavier M / de Gruyter, Heidi L M / Boomaars-van der Zanden, A Linda / van der Meer, Yvonne / Snijder, Eric J / Kikkert, Marjolein / Myeni, Sebenzile K

Viruses

2024 Volume 16, Issue 2

Abstract: Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, ...

Abstract	Mitochondrial antiviral signaling protein (MAVS) is a crucial signaling adaptor in the sensing of positive-sense RNA viruses and the subsequent induction of the innate immune response. Coronaviruses have evolved multiple mechanisms to evade this response, amongst others, through their main protease (M
MeSH term(s)	Middle East Respiratory Syndrome Coronavirus ; Immunity, Innate ; Interferon-beta/metabolism ; Peptide Hydrolases ; Antiviral Agents
Chemical Substances	Interferon-beta (77238-31-4) ; Peptide Hydrolases (EC 3.4.-) ; Antiviral Agents
Language	English
Publishing date	2024-02-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v16020256
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Article ; Online: R-Propranolol Has Broad-Spectrum Anti-Coronavirus Activity and Suppresses Factors Involved in Pathogenic Angiogenesis.

Thaler, Melissa / Salgado-Benvindo, Clarisse / Leijs, Anouk / Tas, Ali / Ninaber, Dennis K / Arbiser, Jack L / Snijder, Eric J / van Hemert, Martijn J

International journal of molecular sciences

2023 Volume 24, Issue 5

Abstract: The SARS-CoV-2 pandemic highlighted the need for broad-spectrum antivirals to increase our preparedness. Patients often require treatment by the time that blocking virus replication is less effective. Therefore, therapy should not only aim to inhibit the ...

Abstract	The SARS-CoV-2 pandemic highlighted the need for broad-spectrum antivirals to increase our preparedness. Patients often require treatment by the time that blocking virus replication is less effective. Therefore, therapy should not only aim to inhibit the virus, but also to suppress pathogenic host responses, e.g., leading to microvascular changes and pulmonary damage. Clinical studies have previously linked SARS-CoV-2 infection to pathogenic intussusceptive angiogenesis in the lungs, involving the upregulation of angiogenic factors such as ANGPTL4. The β-blocker propranolol is used to suppress aberrant ANGPTL4 expression in the treatment of hemangiomas. Therefore, we investigated the effect of propranolol on SARS-CoV-2 infection and the expression of ANGPTL4. SARS-CoV-2 upregulated ANGPTL4 in endothelial and other cells, which could be suppressed with R-propranolol. The compound also inhibited the replication of SARS-CoV-2 in Vero-E6 cells and reduced the viral load by up to ~2 logs in various cell lines and primary human airway epithelial cultures. R-propranolol was as effective as S-propranolol but lacks the latter's undesired β-blocker activity. R-propranolol also inhibited SARS-CoV and MERS-CoV. It inhibited a post-entry step of the replication cycle, likely via host factors. The broad-spectrum antiviral effect and suppression of factors involved in pathogenic angiogenesis make R-propranolol an interesting molecule to further explore for the treatment of coronavirus infections.
MeSH term(s)	Animals ; Chlorocebus aethiops ; Humans ; COVID-19 ; Propranolol/pharmacology ; SARS-CoV-2 ; Vero Cells ; Cell Line ; Antiviral Agents/pharmacology ; Virus Replication
Chemical Substances	Propranolol (9Y8NXQ24VQ) ; Antiviral Agents
Language	English
Publishing date	2023-02-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24054588
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Article ; Online: Honokiol Inhibits SARS-CoV-2 Replication in Cell Culture at a Post-Entry Step.

Salgado-Benvindo, Clarisse / Leijs, Anouk A / Thaler, Melissa / Tas, Ali / Arbiser, Jack L / Snijder, Eric J / van Hemert, Martijn J

Microbiology spectrum

2023 Volume 11, Issue 3, Page(s) e0327322

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019, and the resulting pandemic has already caused the death of over 6 million people. There are currently few antivirals approved for treatment of the 2019 coronavirus disease ( ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019, and the resulting pandemic has already caused the death of over 6 million people. There are currently few antivirals approved for treatment of the 2019 coronavirus disease (COVID-19), and more options would be beneficial, not only now but also to increase our preparedness for future coronavirus outbreaks. Honokiol is a small molecule from magnolia trees for which several biological effects have been reported, including anticancer and anti-inflammatory activities. Honokiol has also been shown to inhibit several viruses in cell culture. In this study, we determined that honokiol protected Vero E6 cells from SARS-CoV-2-mediated cytopathic effect, with a 50% effective concentration of 7.8 μM. In viral load reduction assays, honokiol decreased viral RNA copies as well as viral infectious progeny titers. The compound also inhibited SARS-CoV-2 replication in the more relevant human A549 cells expressing angiotensin converting enzyme 2 and transmembrane protease serine 2. Time-of-addition and other assays showed that honokiol inhibited virus replication at a post-entry step of the replication cycle. Honokiol was also effective against more recent variants of SARS-CoV-2, including Omicron, and it inhibited other human coronaviruses as well. Our study suggests that honokiol is an interesting molecule to be evaluated further in animal studies and, when successful, maybe even in clinical trials to investigate its effect on virus replication and pathogenic (inflammatory) host responses.
MeSH term(s)	Animals ; Humans ; SARS-CoV-2 ; COVID-19 ; Antiviral Agents/pharmacology ; Cell Culture Techniques
Chemical Substances	honokiol (11513CCO0N) ; Antiviral Agents
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2807133-5
ISSN	2165-0497 ; 2165-0497
ISSN (online)	2165-0497
ISSN	2165-0497
DOI	10.1128/spectrum.03273-22
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Article ; Online: Structures and functions of coronavirus replication-transcription complexes and their relevance for SARS-CoV-2 drug design.

Malone, Brandon / Urakova, Nadya / Snijder, Eric J / Campbell, Elizabeth A

Nature reviews. Molecular cell biology

2021 Volume 23, Issue 1, Page(s) 21–39

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to cause massive global upheaval. Coronaviruses are positive-strand RNA viruses with an unusually large genome of ~30 kb. They express an RNA- ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to cause massive global upheaval. Coronaviruses are positive-strand RNA viruses with an unusually large genome of ~30 kb. They express an RNA-dependent RNA polymerase and a cohort of other replication enzymes and supporting factors to transcribe and replicate their genomes. The proteins performing these essential processes are prime antiviral drug targets, but drug discovery is hindered by our incomplete understanding of coronavirus RNA synthesis and processing. In infected cells, the RNA-dependent RNA polymerase must coordinate with other viral and host factors to produce both viral mRNAs and new genomes. Recent research aiming to decipher and contextualize the structures, functions and interplay of the subunits of the SARS-CoV-2 replication and transcription complex proteins has burgeoned. In this Review, we discuss recent advancements in our understanding of the molecular basis and complexity of the coronavirus RNA-synthesizing machinery. Specifically, we outline the mechanisms and regulation of RNA translation, replication and transcription. We also discuss the composition of the replication and transcription complexes and their suitability as targets for antiviral therapy.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Drug Design ; Humans ; RNA, Viral/metabolism ; SARS-CoV-2/genetics ; SARS-CoV-2/physiology ; Transcription, Genetic/drug effects ; Virus Replication/drug effects ; Virus Replication/physiology
Chemical Substances	Antiviral Agents ; RNA, Viral
Language	English
Publishing date	2021-11-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-021-00432-z
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Zs.A 5446: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 26: Show issues

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Article ; Online: Highly Potent Antisense Oligonucleotides Locked Nucleic Acid Gapmers Targeting the SARS-CoV-2 RNA Genome.

Dauksaite, Vita / Tas, Ali / Wachowius, Falk / Spruit, Anouk / van Hemert, Martijn J / Snijder, Eric J / van der Veer, Eric P / van Zonneveld, Anton Jan

Nucleic acid therapeutics

2023 Volume 33, Issue 6, Page(s) 381–385

Abstract: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the current worldwide pandemic and the associated coronavirus disease 2019 with potentially lethal outcome. Although effective vaccines strongly contributed to reduce disease ... ...

Abstract	The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the current worldwide pandemic and the associated coronavirus disease 2019 with potentially lethal outcome. Although effective vaccines strongly contributed to reduce disease severity, establishing a toolbox to control current and newly emerging coronaviruses of epidemic concern requires the development of novel therapeutic compounds, to treat severely infected individuals and to prevent virus transmission. Here we present a therapeutic strategy targeting the SARS-CoV-2 RNA genome using antisense oligonucleotides (ASOs). We demonstrate that selected locked nucleic acid gapmers have the potency to reduce the
MeSH term(s)	Humans ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/therapeutic use ; SARS-CoV-2/genetics ; RNA, Viral/genetics ; COVID-19/genetics ; COVID-19/therapy
Chemical Substances	locked nucleic acid ; Oligonucleotides, Antisense ; RNA, Viral
Language	English
Publishing date	2023-09-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2639888-6
ISSN	2159-3345 ; 2159-3337
ISSN (online)	2159-3345
ISSN	2159-3337
DOI	10.1089/nat.2023.0012
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Article ; Online: Double-Membrane Vesicles as Platforms for Viral Replication.

Wolff, Georg / Melia, Charlotte E / Snijder, Eric J / Bárcena, Montserrat

Trends in microbiology

2020 Volume 28, Issue 12, Page(s) 1022–1033

Abstract: Viruses, as obligate intracellular parasites, exploit cellular pathways and resources in a variety of fascinating ways. A striking example of this is the remodelling of intracellular membranes into specialized structures that support the replication of ... ...

Abstract	Viruses, as obligate intracellular parasites, exploit cellular pathways and resources in a variety of fascinating ways. A striking example of this is the remodelling of intracellular membranes into specialized structures that support the replication of positive-sense ssRNA (+RNA) viruses infecting eukaryotes. These distinct forms of virus-induced structures include double-membrane vesicles (DMVs), found during viral infections as diverse and notorious as those of coronaviruses, enteroviruses, noroviruses, or hepatitis C virus. Our understanding of these DMVs has evolved over the past 15 years thanks to advances in imaging techniques and modern molecular biology tools. In this article, we review contemporary understanding of the biogenesis, structure, and function of virus-induced DMVs as well as the open questions posed by these intriguing structures.
MeSH term(s)	Animals ; Coronavirus/physiology ; Enterovirus/physiology ; Hepacivirus/physiology ; Hepatitis C/virology ; Host Microbial Interactions/physiology ; Humans ; Intracellular Membranes/virology ; Norovirus/physiology ; Organelle Biogenesis ; RNA, Viral ; Viral Proteins ; Virus Replication/physiology
Chemical Substances	RNA, Viral ; Viral Proteins
Keywords	covid19
Language	English
Publishing date	2020-06-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2020.05.009
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Zs.A 3738: Show issues

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Article ; Online: The alphavirus nonstructural protein 2 NTPase induces a host translational shut-off through phosphorylation of eEF2 via cAMP-PKA-eEF2K signaling.

Treffers, Emmely E / Tas, Ali / Scholte, Florine E M / de Ru, Arnoud H / Snijder, Eric J / van Veelen, Peter A / van Hemert, Martijn J

PLoS pathogens

2023 Volume 19, Issue 2, Page(s) e1011179

Abstract: Chikungunya virus (CHIKV) is a reemerging alphavirus. Since 2005, it has infected millions of people during outbreaks in Africa, Asia, and South/Central America. CHIKV replication depends on host cell factors at many levels and is expected to have a ... ...

Abstract	Chikungunya virus (CHIKV) is a reemerging alphavirus. Since 2005, it has infected millions of people during outbreaks in Africa, Asia, and South/Central America. CHIKV replication depends on host cell factors at many levels and is expected to have a profound effect on cellular physiology. To obtain more insight into host responses to infection, stable isotope labeling with amino acids in cell culture and liquid chromatography-tandem mass spectrometry were used to assess temporal changes in the cellular phosphoproteome during CHIKV infection. Among the ~3,000 unique phosphorylation sites analyzed, the largest change in phosphorylation status was measured on residue T56 of eukaryotic elongation factor 2 (eEF2), which showed a >50-fold increase at 8 and 12 h p.i. Infection with other alphaviruses (Semliki Forest, Sindbis and Venezuelan equine encephalitis virus (VEEV)) triggered a similarly strong eEF2 phosphorylation. Expression of a truncated form of CHIKV or VEEV nsP2, containing only the N-terminal and NTPase/helicase domains (nsP2-NTD-Hel), sufficed to induce eEF2 phosphorylation, which could be prevented by mutating key residues in the Walker A and B motifs of the NTPase domain. Alphavirus infection or expression of nsP2-NTD-Hel resulted in decreased cellular ATP levels and increased cAMP levels. This did not occur when catalytically inactive NTPase mutants were expressed. The wild-type nsP2-NTD-Hel inhibited cellular translation independent of the C-terminal nsP2 domain, which was previously implicated in directing the virus-induced host shut-off for Old World alphaviruses. We hypothesize that the alphavirus NTPase activates a cellular adenylyl cyclase resulting in increased cAMP levels, thus activating PKA and subsequently eukaryotic elongation factor 2 kinase. This in turn triggers eEF2 phosphorylation and translational inhibition. We conclude that the nsP2-driven increase of cAMP levels contributes to the alphavirus-induced shut-off of cellular protein synthesis that is shared between Old and New World alphaviruses. MS Data are available via ProteomeXchange with identifier PXD009381.
MeSH term(s)	Humans ; Alphavirus/metabolism ; Nucleoside-Triphosphatase/metabolism ; Peptide Elongation Factor 2/metabolism ; Eukaryota ; Phosphorylation ; Chikungunya virus/physiology ; Chikungunya Fever ; Viral Nonstructural Proteins/metabolism ; Virus Replication ; Elongation Factor 2 Kinase/metabolism
Chemical Substances	Nucleoside-Triphosphatase (EC 3.6.1.15) ; Peptide Elongation Factor 2 ; Viral Nonstructural Proteins ; EEF2K protein, human (EC 2.7.1.17) ; Elongation Factor 2 Kinase (EC 2.7.11.20)
Language	English
Publishing date	2023-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011179
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Article: The Curious Case of the Nidovirus Exoribonuclease: Its Role in RNA Synthesis and Replication Fidelity.

Ogando, Natacha S / Ferron, Francois / Decroly, Etienne / Canard, Bruno / Posthuma, Clara C / Snijder, Eric J

Frontiers in microbiology

2019 Volume 10, Page(s) 1813

Abstract: Among RNA viruses, the ... ...

Abstract	Among RNA viruses, the order
Keywords	covid19
Language	English
Publishing date	2019-08-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2019.01813
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Article ; Online: Engineering potent live attenuated coronavirus vaccines by targeted inactivation of the immune evasive viral deubiquitinase.

Myeni, Sebenzile K / Bredenbeek, Peter J / Knaap, Robert C M / Dalebout, Tim J / Morales, Shessy Torres / Sidorov, Igor A / Linger, Marissa E / Oreshkova, Nadia / van Zanen-Gerhardt, Sophie / Zander, Serge A L / Enjuanes, Luis / Sola, Isabel / Snijder, Eric J / Kikkert, Marjolein

Nature communications

2023 Volume 14, Issue 1, Page(s) 1141

Abstract: Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus ... ...

Abstract	Coronaviruses express a papain-like protease (PLpro) that is required for replicase polyprotein maturation and also serves as a deubiquitinating enzyme (DUB). In this study, using a Middle East respiratory syndrome virus (MERS-CoV) PLpro modified virus in which the DUB is selectively inactivated, we show that the PLpro DUB is an important MERS-CoV interferon antagonist and virulence factor. Although the DUB-negative rMERS-CoV
MeSH term(s)	Animals ; Humans ; Mice ; COVID-19 Vaccines ; Deubiquitinating Enzymes ; Papain ; Peptide Hydrolases ; Vaccines, Attenuated ; Vaccine Development
Chemical Substances	COVID-19 Vaccines ; Deubiquitinating Enzymes (EC 3.4.19.12) ; Papain (EC 3.4.22.2) ; Peptide Hydrolases (EC 3.4.-) ; Vaccines, Attenuated
Language	English
Publishing date	2023-02-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-36754-z
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