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Article ; Online: A mitotic stopwatch determines cell fate.

Bertolin, Agustina P / Gottifredi, Vanesa

2024 Volume 383, Issue 6690, Page(s) 1414–1415

Abstract: Surveillance of mitotic timing prevents amplification of damaged cells. ...

Abstract	Surveillance of mitotic timing prevents amplification of damaged cells.
MeSH term(s)	Mitosis ; Cell Proliferation ; Cell Differentiation
Language	English
Publishing date	2024-03-28
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.ado5703
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Article: Under-Replicated DNA: The Byproduct of Large Genomes?

Bertolin, Agustina P / Hoffmann, Jean-Sébastien / Gottifredi, Vanesa

Cancers

2020 Volume 12, Issue 10

Abstract: In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) ... ...

Abstract	In this review, we provide an overview of how proliferating eukaryotic cells overcome one of the main threats to genome stability: incomplete genomic DNA replication during S phase. We discuss why it is currently accepted that double fork stalling (DFS) events are unavoidable events in higher eukaryotes with large genomes and which responses have evolved to cope with its main consequence: the presence of under-replicated DNA (UR-DNA) outside S phase. Particular emphasis is placed on the processes that constrain the detrimental effects of UR-DNA. We discuss how mitotic DNA synthesis (MiDAS), mitotic end joining events and 53BP1 nuclear bodies (53BP1-NBs) deal with such specific S phase DNA replication remnants during the subsequent phases of the cell cycle.
Language	English
Publishing date	2020-09-25
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12102764
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp15 endoribonuclease.

Canal, Berta / Fujisawa, Ryo / McClure, Allison W / Deegan, Tom D / Wu, Mary / Ulferts, Rachel / Weissmann, Florian / Drury, Lucy S / Bertolin, Agustina P / Zeng, Jingkun / Beale, Rupert / Howell, Michael / Labib, Karim / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2465–2479

Abstract: SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered economies of countries and families around the world. Antiviral treatments to combat COVID-19 ... ...

Abstract	SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered economies of countries and families around the world. Antiviral treatments to combat COVID-19 are currently lacking. Remdesivir, the only antiviral drug approved for the treatment of COVID-19, can affect disease severity, but better treatments are needed. SARS-CoV-2 encodes 16 non-structural proteins (nsp) that possess different enzymatic activities with important roles in viral genome replication, transcription and host immune evasion. One key aspect of host immune evasion is performed by the uridine-directed endoribonuclease activity of nsp15. Here we describe the expression and purification of nsp15 recombinant protein. We have developed biochemical assays to follow its activity, and we have found evidence for allosteric behaviour. We screened a custom chemical library of over 5000 compounds to identify nsp15 endoribonuclease inhibitors, and we identified and validated NSC95397 as an inhibitor of nsp15 endoribonuclease in vitro. Although NSC95397 did not inhibit SARS-CoV-2 growth in VERO E6 cells, further studies will be required to determine the effect of nsp15 inhibition on host immune evasion.
MeSH term(s)	Allosteric Regulation ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Endoribonucleases/antagonists & inhibitors ; Endoribonucleases/isolation & purification ; Endoribonucleases/metabolism ; Enzyme Assays ; Fluorescence ; High-Throughput Screening Assays ; In Vitro Techniques ; Kinetics ; Naphthoquinones/pharmacology ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; SARS-CoV-2/growth & development ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Solutions ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/isolation & purification ; Viral Nonstructural Proteins/metabolism
Chemical Substances	2,3-bis(2-hydroxyethylsulfanyl)-(1,4)naphthoquinone ; Antiviral Agents ; Naphthoquinones ; Small Molecule Libraries ; Solutions ; Viral Nonstructural Proteins ; Endoribonucleases (EC 3.1.-) ; nidoviral uridylate-specific endoribonuclease (EC 3.1.-)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210199
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase.

Bertolin, Agustina P / Weissmann, Florian / Zeng, Jingkun / Posse, Viktor / Milligan, Jennifer C / Canal, Berta / Ulferts, Rachel / Wu, Mary / Drury, Lucy S / Howell, Michael / Beale, Rupert / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2425–2443

Abstract: The coronavirus disease 2019 (COVID-19) global pandemic has turned into the largest public health and economic crisis in recent history impacting virtually all sectors of society. There is a need for effective therapeutics to battle the ongoing pandemic. ...

Abstract	The coronavirus disease 2019 (COVID-19) global pandemic has turned into the largest public health and economic crisis in recent history impacting virtually all sectors of society. There is a need for effective therapeutics to battle the ongoing pandemic. Repurposing existing drugs with known pharmacological safety profiles is a fast and cost-effective approach to identify novel treatments. The COVID-19 etiologic agent is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded positive-sense RNA virus. Coronaviruses rely on the enzymatic activity of the replication-transcription complex (RTC) to multiply inside host cells. The RTC core catalytic component is the RNA-dependent RNA polymerase (RdRp) holoenzyme. The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologues in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified three novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Benzoates/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Chlorocebus aethiops ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Drug Evaluation, Preclinical ; Enzyme Assays ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; Holoenzymes/metabolism ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Suramin/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Benzoates ; Bridged Bicyclo Compounds, Heterocyclic ; Holoenzymes ; NS8 protein, SARS-CoV-2 ; Small Molecule Libraries ; Viral Nonstructural Proteins ; 2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid (56887611DJ) ; Suramin (6032D45BEM) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; NSP7 protein, SARS-CoV-2 (EC 2.7.7.48)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210200
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Article ; Online: Rhythmic Behavior Is Controlled by the SRm160 Splicing Factor in

Beckwith, Esteban J / Hernando, Carlos E / Polcowñuk, Sofía / Bertolin, Agustina P / Mancini, Estefania / Ceriani, M Fernanda / Yanovsky, Marcelo J

Genetics

2017 Volume 207, Issue 2, Page(s) 593–607

Abstract: Circadian clocks organize the metabolism, physiology, and behavior of organisms throughout the day-night cycle by controlling daily rhythms in gene expression at the transcriptional and post-transcriptional levels. While many transcription factors ... ...

Abstract	Circadian clocks organize the metabolism, physiology, and behavior of organisms throughout the day-night cycle by controlling daily rhythms in gene expression at the transcriptional and post-transcriptional levels. While many transcription factors underlying circadian oscillations are known, the splicing factors that modulate these rhythms remain largely unexplored. A genome-wide assessment of the alterations of gene expression in a null mutant of the alternative splicing regulator SR-related matrix protein of 160 kDa (SRm160) revealed the extent to which alternative splicing impacts on behavior-related genes. We show that
MeSH term(s)	Animals ; Brain/cytology ; Brain/metabolism ; Brain/physiology ; Circadian Rhythm ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/physiology ; Locomotion ; Neurons/metabolism ; Period Circadian Proteins/genetics ; Period Circadian Proteins/metabolism ; RNA Splicing ; RNA Splicing Factors/genetics ; RNA Splicing Factors/metabolism
Chemical Substances	Drosophila Proteins ; PER protein, Drosophila ; Period Circadian Proteins ; RNA Splicing Factors
Language	English
Publishing date	2017-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1534/genetics.117.300139
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Article ; Online: Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation.

Vallerga, María Belén / Mansilla, Sabrina F / Federico, María Belén / Bertolin, Agustina P / Gottifredi, Vanesa

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 48, Page(s) E6624–33

Abstract: After UV irradiation, DNA polymerases specialized in translesion DNA synthesis (TLS) aid DNA replication. However, it is unclear whether other mechanisms also facilitate the elongation of UV-damaged DNA. We wondered if Rad51 recombinase (Rad51), a factor ...

Abstract	After UV irradiation, DNA polymerases specialized in translesion DNA synthesis (TLS) aid DNA replication. However, it is unclear whether other mechanisms also facilitate the elongation of UV-damaged DNA. We wondered if Rad51 recombinase (Rad51), a factor that escorts replication forks, aids replication across UV lesions. We found that depletion of Rad51 impairs S-phase progression and increases cell death after UV irradiation. Interestingly, Rad51 and the TLS polymerase polη modulate the elongation of nascent DNA in different ways, suggesting that DNA elongation after UV irradiation does not exclusively rely on TLS events. In particular, Rad51 protects the DNA synthesized immediately before UV irradiation from degradation and avoids excessive elongation of nascent DNA after UV irradiation. In Rad51-depleted samples, the degradation of DNA was limited to the first minutes after UV irradiation and required the exonuclease activity of the double strand break repair nuclease (Mre11). The persistent dysregulation of nascent DNA elongation after Rad51 knockdown required Mre11, but not its exonuclease activity, and PrimPol, a DNA polymerase with primase activity. By showing a crucial contribution of Rad51 to the synthesis of nascent DNA, our results reveal an unanticipated complexity in the regulation of DNA elongation across UV-damaged templates.
MeSH term(s)	Cell Cycle ; Cell Death ; Cell Line, Tumor ; Cell Survival ; DNA/radiation effects ; DNA Breaks, Double-Stranded ; DNA Primase/physiology ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/physiology ; DNA-Directed DNA Polymerase/metabolism ; DNA-Directed DNA Polymerase/physiology ; Disease Progression ; Dose-Response Relationship, Radiation ; HeLa Cells ; Humans ; MRE11 Homologue Protein ; Multifunctional Enzymes/physiology ; RNA, Small Interfering/metabolism ; Rad51 Recombinase/physiology ; Ultraviolet Rays
Chemical Substances	DNA-Binding Proteins ; MRE11 protein, human ; Multifunctional Enzymes ; RNA, Small Interfering ; DNA (9007-49-2) ; DNA Primase (EC 2.7.7.-) ; PrimPol protein, human (EC 2.7.7.-) ; RAD51 protein, human (EC 2.7.7.-) ; Rad51 Recombinase (EC 2.7.7.-) ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; POLK protein, human (EC 2.7.7.7) ; Rad30 protein (EC 2.7.7.7) ; MRE11 Homologue Protein (EC 3.1.-)
Language	English
Publishing date	2015-11-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1508543112
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Article ; Online: Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp15 Endoribonuclease

Beale, Rupert / Bertolin, Agustina P / Canal, Berta / Deegan, Tom D / Diffley, John FX / Drury, Lucy S / Fujisawa, Ryo / Howell, Michael / Labib, Karim / McClure, Allison W / Ulferts, Rachel / Weissmann, Florian / Wu, Mary / Zeng, Jingkun

bioRxiv

Abstract: SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered the economies of countries and families around the world. Antiviral treatments to combat COVID- ... ...

Abstract	SARS-CoV-2 is responsible for COVID-19, a human disease that has caused over 2 million deaths, stretched health systems to near-breaking point and endangered the economies of countries and families around the world. Antiviral treatments to combat COVID-19 are currently lacking. Remdesivir, the only antiviral drug approved for the treatment of COVID-19, can affect disease severity, but better treatments are needed. SARS-CoV-2 encodes 16 non-structural proteins (nsp) that possess different enzymatic activities with important roles in viral genome replication, transcription and host immune evasion. One key aspect of host immune evasion is performed by the uridine-directed endoribonuclease activity of nsp15. Here we describe the expression and purification of nsp15 recombinant protein. We have developed biochemical assays to follow its activity, and we have found evidence for allosteric behaviour. We screened a custom chemical library of over 5000 compounds to identify nsp15 endoribonuclease inhibitors, and we identified and validated NSC95397 as an inhibitor of nsp15 endoribonuclease in vitro. Although NSC95397 did not inhibit SARS-CoV-2 growth in VERO E6 cells, further studies will be required to determine the effect of nsp15 inhibition on host immune evasion.
Keywords	covid19
Language	English
Publishing date	2021-04-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.07.438811
Database	COVID19

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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp13 helicase.

Zeng, Jingkun / Weissmann, Florian / Bertolin, Agustina P / Posse, Viktor / Canal, Berta / Ulferts, Rachel / Wu, Mary / Harvey, Ruth / Hussain, Saira / Milligan, Jennifer C / Roustan, Chloe / Borg, Annabel / McCoy, Laura / Drury, Lucy S / Kjaer, Svend / McCauley, John / Howell, Michael / Beale, Rupert / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2405–2423

Abstract: The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health challenge. While the efficacy of vaccines against emerging and future virus variants remains unclear, there is a need for therapeutics. Repurposing existing drugs represents a promising and potentially rapid opportunity to find novel antivirals against SARS-CoV-2. The virus encodes at least nine enzymatic activities that are potential drug targets. Here, we have expressed, purified and developed enzymatic assays for SARS-CoV-2 nsp13 helicase, a viral replication protein that is essential for the coronavirus life cycle. We screened a custom chemical library of over 5000 previously characterized pharmaceuticals for nsp13 inhibitors using a fluorescence resonance energy transfer-based high-throughput screening approach. From this, we have identified FPA-124 and several suramin-related compounds as novel inhibitors of nsp13 helicase activity in vitro. We describe the efficacy of these drugs using assays we developed to monitor SARS-CoV-2 growth in Vero E6 cells.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Enzyme Assays ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; RNA Helicases/antagonists & inhibitors ; RNA Helicases/metabolism ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Suramin/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Small Molecule Libraries ; Viral Nonstructural Proteins ; Suramin (6032D45BEM) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210201
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.

Canal, Berta / McClure, Allison W / Curran, Joseph F / Wu, Mary / Ulferts, Rachel / Weissmann, Florian / Zeng, Jingkun / Bertolin, Agustina P / Milligan, Jennifer C / Basu, Souradeep / Drury, Lucy S / Deegan, Tom D / Fujisawa, Ryo / Roberts, Emma L / Basier, Clovis / Labib, Karim / Beale, Rupert / Howell, Michael / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2445–2464

Abstract: SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective ... ...

Abstract	SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Aurintricarboxylic Acid/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Enzyme Assays ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/metabolism ; Fluorescence ; High-Throughput Screening Assays ; Patulin/pharmacology ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism ; Viral Regulatory and Accessory Proteins/antagonists & inhibitors ; Viral Regulatory and Accessory Proteins/metabolism
Chemical Substances	Antiviral Agents ; NSP10 protein, SARS-CoV-2 ; Small Molecule Libraries ; Viral Nonstructural Proteins ; Viral Regulatory and Accessory Proteins ; Aurintricarboxylic Acid (4431-00-9) ; Patulin (95X2BV4W8R) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210198
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Article ; Online: Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp12/7/8 RNA-dependent RNA Polymerase

Beale, Rupert / Bertolin, Agustina P / Canal, Berta / Diffley, John FX / Drury, Lucy S / Howell, Michael / Milligan, Jennifer / Posse, Viktor / Ulferts, Rachel / Weissmann, Florian / Wu, Mary / Zeng, Jingkun

bioRxiv

Abstract	The coronavirus disease 2019 (COVID-19) global pandemic has turned into the largest public health and economic crisis in recent history impacting virtually all sectors of society. There is a need for effective therapeutics to battle the ongoing pandemic. Repurposing existing drugs with known pharmacological safety profiles is a fast and cost-effective approach to identify novel treatments. The COVID-19 etiologic agent is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded positive-sense RNA virus. Coronaviruses rely on the enzymatic activity of the replication-transcription complex (RTC) to multiply inside host cells. The RTC core catalytic component is the RNA-dependent RNA polymerase (RdRp) holoenzyme. The RdRp is one of the key druggable targets for CoVs due to its essential role in viral replication, high degree of sequence and structural conservation and the lack of homologs in human cells. Here, we have expressed, purified and biochemically characterised active SARS-CoV-2 RdRp complexes. We developed a novel fluorescence resonance energy transfer (FRET)-based strand displacement assay for monitoring SARS-CoV-2 RdRp activity suitable for a high-throughput format. As part of a larger research project to identify inhibitors for all the enzymatic activities encoded by SARS-CoV-2, we used this assay to screen a custom chemical library of over 5000 approved and investigational compounds for novel SARS-CoV-2 RdRp inhibitors. We identified 3 novel compounds (GSK-650394, C646 and BH3I-1) and confirmed suramin and suramin-like compounds as in vitro SARS-CoV-2 RdRp activity inhibitors. We also characterised the antiviral efficacy of these drugs in cell-based assays that we developed to monitor SARS-CoV-2 growth.
Keywords	covid19
Language	English
Publishing date	2021-04-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.07.438807
Database	COVID19

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