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Article: A fluorescence-based high throughput-screening assay for the SARS-CoV RNA synthesis complex

Eydoux, Cecilia / Fattorini, Veronique / Shannon, Ashleigh / Le, Thi-Tuyet-Nhung / Didier, Bruno / Canard, Bruno / Guillemot, Jean-Claude

Journal of virological methods. 2021 Feb., v. 288

2021

Abstract: The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire ... ...

Abstract	The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire antiviral strategies, as conserved viral enzymes (eg., viral proteases and RNA-dependent RNA polymerases) represent targets of choice. Since 2003, much effort has been expended in the characterization of the SARS-CoV replication/transcription machinery. Until recently, a pure and highly active preparation of SARS-CoV recombinant RNA synthesis machinery was not available, impeding target-based high throughput screening of drug candidates against this viral family. The current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic revealed a new pathogen whose RNA synthesis machinery is highly (>96 % aa identity) homologous to SARS-CoV. This phylogenetic relatedness highlights the potential use of conserved replication enzymes to discover inhibitors against this significant pathogen, which in turn, contributes to scientific preparedness against emerging viruses. Here, we report the use of a purified and highly active SARS-CoV replication/transcription complex (RTC) to set-up a high-throughput screening of Coronavirus RNA synthesis inhibitors. The screening of a small (1520 compounds) chemical library of FDA-approved drugs demonstrates the robustness of our assay and will allow to speed-up drug discovery against the SARS-CoV-2.
Keywords	RNA ; Severe acute respiratory syndrome coronavirus ; Severe acute respiratory syndrome coronavirus 2 ; drugs ; humans ; pandemic ; pathogens ; phylogeny ; proteinases
Language	English
Dates of publication	2021-02
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	8013-5
ISSN	1879-0984 ; 0166-0934
ISSN (online)	1879-0984
ISSN	0166-0934
DOI	10.1016/j.jviromet.2020.114013
Database	NAL-Catalogue (AGRICOLA)

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Article: A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro.

De Castro, Sonia / Stevaert, Annelies / Maldonado, Miguel / Delpal, Adrien / Vandeput, Julie / Van Loy, Benjamin / Eydoux, Cecilia / Guillemot, Jean-Claude / Decroly, Etienne / Gago, Federico / Canard, Bruno / Camarasa, Maria-Jose / Velázquez, Sonsoles / Naesens, Lieve

Pharmaceuticals (Basel, Switzerland)

2022 Volume 15, Issue 8

Abstract: There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity ...

Abstract	There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2'-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (M
Language	English
Publishing date	2022-08-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph15081021
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Carneic Acids from an Endophytic

Peyrat, Laure-Anne / Eparvier, Véronique / Eydoux, Cécilia / Guillemot, Jean-Claude / Litaudon, Marc / Stien, Didier

Journal of natural products

2020 Volume 83, Issue 8, Page(s) 2330–2336

Abstract: Thirteen carneic acids were isolated from the fungal ... ...

Abstract	Thirteen carneic acids were isolated from the fungal endophyte
MeSH term(s)	Antiviral Agents/chemistry ; Antiviral Agents/isolation & purification ; Antiviral Agents/pharmacology ; Cell Line ; Dengue Virus/drug effects ; Dengue Virus/enzymology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/isolation & purification ; Enzyme Inhibitors/pharmacology ; Humans ; Molecular Structure ; Phomopsis/chemistry ; Polyketides/chemistry ; Polyketides/isolation & purification ; Polyketides/pharmacology ; Spectrum Analysis/methods ; Viral Proteins/antagonists & inhibitors
Chemical Substances	Antiviral Agents ; Enzyme Inhibitors ; Polyketides ; Viral Proteins
Language	English
Publishing date	2020-07-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.9b01169
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Article ; Online: A fluorescence-based high throughput-screening assay for the SARS-CoV RNA synthesis complex.

Eydoux, Cecilia / Fattorini, Veronique / Shannon, Ashleigh / Le, Thi-Tuyet-Nhung / Didier, Bruno / Canard, Bruno / Guillemot, Jean-Claude

Journal of virological methods

2020 Volume 288, Page(s) 114013

Abstract	The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire antiviral strategies, as conserved viral enzymes (eg., viral proteases and RNA-dependent RNA polymerases) represent targets of choice. Since 2003, much effort has been expended in the characterization of the SARS-CoV replication/transcription machinery. Until recently, a pure and highly active preparation of SARS-CoV recombinant RNA synthesis machinery was not available, impeding target-based high throughput screening of drug candidates against this viral family. The current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic revealed a new pathogen whose RNA synthesis machinery is highly (>96 % aa identity) homologous to SARS-CoV. This phylogenetic relatedness highlights the potential use of conserved replication enzymes to discover inhibitors against this significant pathogen, which in turn, contributes to scientific preparedness against emerging viruses. Here, we report the use of a purified and highly active SARS-CoV replication/transcription complex (RTC) to set-up a high-throughput screening of Coronavirus RNA synthesis inhibitors. The screening of a small (1520 compounds) chemical library of FDA-approved drugs demonstrates the robustness of our assay and will allow to speed-up drug discovery against the SARS-CoV-2.
MeSH term(s)	Antiviral Agents/pharmacology ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Enzyme Activation ; Fluorescent Dyes ; High-Throughput Screening Assays/methods ; High-Throughput Screening Assays/standards ; Humans ; Inhibitory Concentration 50 ; RNA, Messenger/genetics ; RNA, Viral ; RNA-Dependent RNA Polymerase/metabolism ; SARS Virus/genetics ; Severe Acute Respiratory Syndrome/diagnosis ; Severe Acute Respiratory Syndrome/genetics ; Templates, Genetic
Chemical Substances	Antiviral Agents ; Fluorescent Dyes ; RNA, Messenger ; RNA, Viral ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Keywords	covid19
Language	English
Publishing date	2020-11-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	8013-5
ISSN	1879-0984 ; 0166-0934
ISSN (online)	1879-0984
ISSN	0166-0934
DOI	10.1016/j.jviromet.2020.114013
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Article: Carneic Acids from an Endophytic Phomopsis sp. as Dengue Virus Polymerase Inhibitors

Peyrat, Laure-Anne / Eparvier, Véronique / Eydoux, Cécilia / Guillemot, Jean-Claude / Litaudon, Marc / Stien, Didier

Journal of natural products. 2020 July 20, v. 83, no. 8

2020

Abstract: Thirteen carneic acids were isolated from the fungal endophyte Phomopsis sp. SNB-LAP1-7-32. Their structures were identified by mass spectrometry and extensive one- and two-dimensional NMR spectroscopy and through comparison with data reported in the ... ...

Abstract	Thirteen carneic acids were isolated from the fungal endophyte Phomopsis sp. SNB-LAP1-7-32. Their structures were identified by mass spectrometry and extensive one- and two-dimensional NMR spectroscopy and through comparison with data reported in the literature. Compounds 1–13 were investigated for their antipolymerase activities against DENV polymerase and Zika NS5. Five of them exhibited significant inhibition of dengue polymerase with IC₅₀ values in the 10 to 20 μM range without cytotoxicity. None inhibited Zika virus NS5 protein.
Keywords	Dengue virus ; Diaporthe ; Zika virus ; cytotoxicity ; dengue ; endophytes ; fungi ; mass spectrometry ; nuclear magnetic resonance spectroscopy
Language	English
Dates of publication	2020-0720
Size	p. 2330-2336.
Publishing place	American Chemical Society and American Society of Pharmacognosy
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	304325-3
ISSN	1520-6025 ; 0163-3864
ISSN (online)	1520-6025
ISSN	0163-3864
DOI	10.1021/acs.jnatprod.9b01169
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: System-oriented optimization of multi-target 2,6-diaminopurine derivatives: Easily accessible broad-spectrum antivirals active against flaviviruses, influenza virus and SARS-CoV-2.

Vicenti, Ilaria / Martina, Maria Grazia / Boccuto, Adele / De Angelis, Marta / Giavarini, Giorgia / Dragoni, Filippo / Marchi, Serena / Trombetta, Claudia Maria / Crespan, Emmanuele / Maga, Giovanni / Eydoux, Cecilia / Decroly, Etienne / Montomoli, Emanuele / Nencioni, Lucia / Zazzi, Maurizio / Radi, Marco

European journal of medicinal chemistry

2021 Volume 224, Page(s) 113683

Abstract: The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum antiviral agents ...

Abstract	The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-emerging. Starting from previously identified anti-flavivirus hits, we report herein the identification of promising BSAAs by submitting the multi-target 2,6-diaminopurine chemotype to a system-oriented optimization based on phenotypic screening on cell cultures infected with different viruses. Among the synthesized compounds, 6i showed low micromolar potency against Dengue, Zika, West Nile and Influenza A viruses (IC
MeSH term(s)	Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Flavivirus/drug effects ; Molecular Targeted Therapy ; Orthomyxoviridae/drug effects ; Purines/chemistry ; Purines/pharmacology ; SARS-CoV-2/drug effects ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Purines
Language	English
Publishing date	2021-07-05
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2021.113683
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Article ; Online: Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites.

Shannon, Ashleigh / Le, Nhung Thi-Tuyet / Selisko, Barbara / Eydoux, Cecilia / Alvarez, Karine / Guillemot, Jean-Claude / Decroly, Etienne / Peersen, Olve / Ferron, Francois / Canard, Bruno

Antiviral research

2020 Volume 178, Page(s) 104793

Abstract: The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target ...

Abstract	The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high sequence and structural conservation. To date, the most promising broad-spectrum class of viral RdRp inhibitors are nucleoside analogues (NAs), with over 25 approved for the treatment of several medically important viral diseases. However, Coronaviruses stand out as a particularly challenging case for NA drug design due to the presence of an exonuclease (ExoN) domain capable of excising incorporated NAs and thus providing resistance to many of these available antivirals. Here we use the available structures of the SARS-CoV RdRp and ExoN proteins, as well as Lassa virus N exonuclease to derive models of catalytically competent SARS-CoV-2 enzymes. We then map a promising NA candidate, GS-441524 (the active metabolite of Remdesivir) to the nucleoside active site of both proteins, identifying the residues important for nucleotide recognition, discrimination, and excision. Interestingly, GS-441524 addresses both enzyme active sites in a manner consistent with significant incorporation, delayed chain termination, and altered excision due to the ribose 1'-CN group, which may account for the increased antiviral effect compared to other available analogues. Additionally, we propose structural and function implications of two previously identified RdRp resistance mutations in relation to resistance against Remdesivir. This study highlights the importance of considering the balance between incorporation and excision properties of NAs between the RdRp and ExoN.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/chemistry ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/chemistry ; Alanine/pharmacology ; Antimetabolites/chemistry ; Antimetabolites/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Betacoronavirus/chemistry ; Betacoronavirus/drug effects ; Betacoronavirus/genetics ; Betacoronavirus/metabolism ; COVID-19 ; Catalytic Domain ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Coronavirus RNA-Dependent RNA Polymerase ; Drug Resistance, Viral ; Exoribonucleases/chemistry ; Exoribonucleases/genetics ; Exoribonucleases/metabolism ; Humans ; Models, Molecular ; Mutation ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/virology ; Protein Conformation ; RNA, Viral/chemistry ; RNA, Viral/genetics ; RNA-Dependent RNA Polymerase/chemistry ; RNA-Dependent RNA Polymerase/genetics ; RNA-Dependent RNA Polymerase/metabolism ; SARS-CoV-2 ; Structure-Activity Relationship ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antimetabolites ; Antiviral Agents ; RNA, Viral ; Viral Nonstructural Proteins ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; nsp14 protein, SARS coronavirus (EC 2.1.1.56) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Exoribonucleases (EC 3.1.-) ; Alanine (OF5P57N2ZX)
Keywords	covid19
Language	English
Publishing date	2020-04-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2020.104793
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Article ; Online: A Fluorescence-based High Throughput-Screening assay for the SARS-CoV RNA synthesis complex

Eydoux, Cecilia / Fattorini, Veronique / Shannon, Ashleigh / Le, Thi-Tuyet-Nhung / Didier, Bruno / Canard, Bruno / Guillemot, Jean-Claude

bioRxiv

Abstract	The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) emergence in 2003 introduced the first serious human coronavirus pathogen to an unprepared world. To control emerging viruses, existing successful anti(retro)viral therapies can inspire antiviral strategies, as conserved viral enzymes (eg., viral proteases and RNA-dependent RNA polymerases) represent targets of choice. Since 2003, much effort has been expended in the characterization of the SARS-CoV replication/transcription machinery. Until recently, a pure and highly active preparation of SARS-CoV recombinant RNA synthesis machinery was not available, impeding target-based high throughput screening of drug candidates against this viral family. The current Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic revealed a new pathogen whose RNA synthesis machinery is highly (>96% aa identity) homologous to SARS-CoV. This phylogenetic relatedness highlights the potential use of conserved replication enzymes to discover inhibitors against this significant pathogen, which in turn, contributes to scientific preparedness against emerging viruses. Here, we report the use of a purified and highly active SARS-CoV replication/transcription complex (RTC) to set-up a high-throughput screening of Coronavirus RNA synthesis inhibitors. The screening of a small (1,520 compounds) chemical library of FDA-approved drugs demonstrates the robustness of our assay and will allow to speed-up drug repositioning or novel drug discovery against the SARS-CoV-2. Principle of SARS-CoV RNA synthesis detection by a fluorescence-based high throughput screening assay Highlights - A new SARS-CoV non radioactive RNA polymerase assay is described - The robotized assay is suitable to identify RdRp inhibitors based on HTS
Keywords	covid19
Publisher	BioRxiv; WHO
Document type	Article ; Online
DOI	10.1101/2020.07.07.192005
Database	COVID19

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Article ; Online: Betulinic Acid, The First Lupane-Type Triterpenoid Isolated from Both a Phomopsis sp. and Its Host Plant Diospyros carbonaria Benoist.

Peyrat, Laure-Anne / Eparvier, Véronique / Eydoux, Cécilia / Guillemot, Jean-Claude / Litaudon, Marc / Stien, Didier

Chemistry & biodiversity

2017 Volume 14, Issue 1

Abstract: Following a biological screening using a dengue replicon virus-cell-based assay, Diospyros carbonaria AcOEt extract was investigated, affording six known lupane-type triterpenoids endowed with anti-DENV-2 NS5 polymerase activity. The study of the ... ...

Abstract	Following a biological screening using a dengue replicon virus-cell-based assay, Diospyros carbonaria AcOEt extract was investigated, affording six known lupane-type triterpenoids endowed with anti-DENV-2 NS5 polymerase activity. The study of the associated microbial community of this species permitted us to identify 38 endophytes belonging to five different orders. Nine out of these 38 strains showed significant activity on the dengue replicon assay. The chemical investigation of the most active one, Phomopsis sp. SNB-LAP1-7-32, led to the isolation of betulinic acid, an anti-viral secondary metabolite isolated previously from the host plant. This result is the first example of a lupane-type triterpenoid isolated from both an endophyte and its host plant. Its presence in the Phomopsis strain may result from gene transfer and/or specific niche selection.
MeSH term(s)	Antiviral Agents/isolation & purification ; Antiviral Agents/pharmacology ; Ascomycota/chemistry ; Diospyros/chemistry ; Endophytes/chemistry ; Triterpenes/isolation & purification ; Triterpenes/pharmacology
Chemical Substances	Antiviral Agents ; Triterpenes ; lupane (464-99-3) ; betulinic acid (4G6A18707N)
Language	English
Publishing date	2017-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2139001-0
ISSN	1612-1880 ; 1612-1872
ISSN (online)	1612-1880
ISSN	1612-1872
DOI	10.1002/cbdv.201600171
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Article ; Online: AT-752 targets multiple sites and activities on the Dengue virus replication enzyme NS5.

Antiviral research

2023 Volume 212, Page(s) 105574

Abstract: AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2'-methyl-2'-fluoro guanosine 5'-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show ... ...

Abstract	AT-752 is a guanosine analogue prodrug active against dengue virus (DENV). In infected cells, it is metabolized into 2'-methyl-2'-fluoro guanosine 5'-triphosphate (AT-9010) which inhibits RNA synthesis in acting as a RNA chain terminator. Here we show that AT-9010 has several modes of action on DENV full-length NS5. AT-9010 does not inhibit the primer pppApG synthesis step significantly. However, AT-9010 targets two NS5-associated enzyme activities, the RNA 2'-O-MTase and the RNA-dependent RNA polymerase (RdRp) at its RNA elongation step. Crystal structure and RNA methyltransferase (MTase) activities of the DENV 2 MTase domain in complex with AT-9010 at 1.97 Å resolution shows the latter bound to the GTP/RNA-cap binding site, accounting for the observed inhibition of 2'-O but not N7-methylation activity. AT-9010 is discriminated ∼10 to 14-fold against GTP at the NS5 active site of all four DENV1-4 NS5 RdRps, arguing for significant inhibition through viral RNA synthesis termination. In Huh-7 cells, DENV1-4 are equally sensitive to AT-281, the free base of AT-752 (EC
MeSH term(s)	Humans ; Dengue/drug therapy ; Dengue Virus/physiology ; Guanosine/pharmacology ; Guanosine/metabolism ; Guanosine Triphosphate/metabolism ; RNA, Viral/metabolism ; Viral Nonstructural Proteins/genetics ; Virus Replication
Chemical Substances	Guanosine (12133JR80S) ; Guanosine Triphosphate (86-01-1) ; RNA, Viral ; Viral Nonstructural Proteins ; AT-752
Language	English
Publishing date	2023-03-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2023.105574
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