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Article ; Online: Rad50 zinc hook functions as a constitutive dimerization module interchangeable with SMC hinge

Hisashi Tatebe / Chew Theng Lim / Hiroki Konno / Kazuhiro Shiozaki / Akira Shinohara / Takayuki Uchihashi / Asako Furukohri

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 11

Abstract: The Mre11/Rad50 complex, which functions in genome surveillance, possesses antiparallel coiled-coil arms forming a ring-like structure similar to that of the SMC family proteins. Here the authors find that the Rad50 zinc hook functions similarly to the ... ...

Abstract	The Mre11/Rad50 complex, which functions in genome surveillance, possesses antiparallel coiled-coil arms forming a ring-like structure similar to that of the SMC family proteins. Here the authors find that the Rad50 zinc hook functions similarly to the hinge of the SMC protein, and that the ring structure of the Mre11/Rad50 dimer also opens by disconnecting its globular head domains.
Keywords	Science ; Q
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Rad50 zinc hook functions as a constitutive dimerization module interchangeable with SMC hinge

Hisashi Tatebe / Chew Theng Lim / Hiroki Konno / Kazuhiro Shiozaki / Akira Shinohara / Takayuki Uchihashi / Asako Furukohri

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 11

Abstract	The Mre11/Rad50 complex, which functions in genome surveillance, possesses antiparallel coiled-coil arms forming a ring-like structure similar to that of the SMC family proteins. Here the authors find that the Rad50 zinc hook functions similarly to the hinge of the SMC protein, and that the ring structure of the Mre11/Rad50 dimer also opens by disconnecting its globular head domains.
Keywords	Science ; Q
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Rad50 zinc hook functions as a constitutive dimerization module interchangeable with SMC hinge.

Tatebe, Hisashi / Lim, Chew Theng / Konno, Hiroki / Shiozaki, Kazuhiro / Shinohara, Akira / Uchihashi, Takayuki / Furukohri, Asako

Nature communications

2020 Volume 11, Issue 1, Page(s) 370

Abstract: The human Mre11/Rad50 complex is one of the key factors in genome maintenance pathways. Previous nanoscale imaging by atomic force microscopy (AFM) showed that the ring-like structure of the human Mre11/Rad50 complex transiently opens at the zinc hook of ...

Abstract	The human Mre11/Rad50 complex is one of the key factors in genome maintenance pathways. Previous nanoscale imaging by atomic force microscopy (AFM) showed that the ring-like structure of the human Mre11/Rad50 complex transiently opens at the zinc hook of Rad50. However, imaging of the human Mre11/Rad50 complex by high-speed AFM shows that the Rad50 coiled-coil arms are consistently bridged by the dimerized hooks while the Mre11/Rad50 ring opens by disconnecting the head domains; resembling other SMC proteins such as cohesin or condensin. These architectural features are conserved in the yeast and bacterial Mre11/Rad50 complexes. Yeast strains harboring the chimeric Mre11/Rad50 complex containing the SMC hinge of bacterial condensin MukB instead of the RAD50 hook properly functions in DNA repair. We propose that the basic role of the Rad50 hook is similar to that of the SMC hinge, which serves as rather stable dimerization interface.
MeSH term(s)	Acid Anhydride Hydrolases/chemistry ; Acid Anhydride Hydrolases/metabolism ; Adenosine Triphosphatases ; Animals ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/chemistry ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/metabolism ; Dimerization ; Escherichia coli/metabolism ; Homologous Recombination ; Humans ; MRE11 Homologue Protein/chemistry ; MRE11 Homologue Protein/metabolism ; Microscopy, Atomic Force ; Multiprotein Complexes ; Nuclear Proteins/chemistry ; Nuclear Proteins/metabolism ; Protein Binding ; Protein Conformation ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; Sf9 Cells ; Zinc/metabolism ; Cohesins
Chemical Substances	Cell Cycle Proteins ; Chromosomal Proteins, Non-Histone ; DNA-Binding Proteins ; MRE11 protein, human ; Multiprotein Complexes ; NBN protein, human ; Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; condensin complexes ; MRE11 Homologue Protein (EC 3.1.-) ; Acid Anhydride Hydrolases (EC 3.6.-) ; RAD50 protein, human (EC 3.6.-) ; Adenosine Triphosphatases (EC 3.6.1.-) ; Zinc (J41CSQ7QDS)
Language	English
Publishing date	2020-01-17
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/s41467-019-14025-0
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Article ; Online: A novel mode of nuclease action is revealed by the bacterial Mre11/Rad50 complex.

Lim, Chew Theng / Lai, Pey Jiun / Leach, David R F / Maki, Hisaji / Furukohri, Asako

Nucleic acids research

2015 Volume 43, Issue 20, Page(s) 9804–9816

Abstract: The Mre11/Rad50 complex is a central player in various genome maintenance pathways. Here, we report a novel mode of nuclease action found for the Escherichia coli Mre11/Rad50 complex, SbcC2/D2 complex (SbcCD). SbcCD cuts off the top of a cruciform DNA by ...

Abstract	The Mre11/Rad50 complex is a central player in various genome maintenance pathways. Here, we report a novel mode of nuclease action found for the Escherichia coli Mre11/Rad50 complex, SbcC2/D2 complex (SbcCD). SbcCD cuts off the top of a cruciform DNA by making incisions on both strands and continues cleaving the dsDNA stem at ∼10-bp intervals. Using linear-shaped DNA substrates, we observed that SbcCD cleaved dsDNA using this activity when the substrate was 110 bp long, but that on shorter substrates the cutting pattern was changed to that predicted for the activity of a 3'-5' exonuclease. Our results suggest that SbcCD processes hairpin and linear dsDNA ends with this novel DNA end-dependent binary endonuclease activity in response to substrate length rather than using previously reported activities. We propose a model for this mode of nuclease action, which provides new insight into SbcCD activity at a dsDNA end.
MeSH term(s)	DNA/chemistry ; DNA/metabolism ; DNA Cleavage ; DNA, Cruciform/metabolism ; Deoxyribonucleases/metabolism ; Endodeoxyribonucleases/metabolism ; Escherichia coli Proteins/metabolism ; Exonucleases/metabolism
Chemical Substances	DNA, Cruciform ; Escherichia coli Proteins ; SbcC protein, E coli ; DNA (9007-49-2) ; Deoxyribonucleases (EC 3.1.-) ; Endodeoxyribonucleases (EC 3.1.-) ; Exonucleases (EC 3.1.-) ; sbcD protein, E coli (EC 3.1.-)
Language	English
Publishing date	2015-11-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkv855
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease.

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2499–2515

Abstract: The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now ...

Abstract	The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.
MeSH term(s)	Amino Acid Chloromethyl Ketones/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Azoles/pharmacology ; Chlorocebus aethiops ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/genetics ; Coronavirus 3C Proteases/isolation & purification ; Coronavirus 3C Proteases/metabolism ; Drug Evaluation, Preclinical ; Enzyme Assays ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; Isoindoles ; Leupeptins/pharmacology ; Organoselenium Compounds/pharmacology ; Peptidomimetics ; RNA-Binding Proteins/metabolism ; 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/metabolism
Chemical Substances	Amino Acid Chloromethyl Ketones ; Antiviral Agents ; Azoles ; Isoindoles ; Leupeptins ; NSP9 protein, SARS-CoV-2 ; Organoselenium Compounds ; Peptidomimetics ; RNA-Binding Proteins ; Small Molecule Libraries ; Viral Nonstructural Proteins ; acetylleucyl-leucyl-norleucinal (110044-82-1) ; ebselen (40X2P7DPGH) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2021-06-24
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/BCJ20210197
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease.

Lim, Chew Theng / Tan, Kang Wei / Wu, Mary / Ulferts, Rachel / Armstrong, Lee A / Ozono, Eiko / Drury, Lucy S / Milligan, Jennifer C / Zeisner, Theresa U / Zeng, Jingkun / Weissmann, Florian / Canal, Berta / Bineva-Todd, Ganka / Howell, Michael / O'Reilly, Nicola / Beale, Rupert / Kulathu, Yogesh / Labib, Karim / Diffley, John F X

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2517–2531

Abstract: The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less ... ...

Abstract	The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Aniline Compounds/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Benzamides/pharmacology ; Chlorocebus aethiops ; Coronavirus Papain-Like Proteases/antagonists & inhibitors ; Coronavirus Papain-Like Proteases/genetics ; Coronavirus Papain-Like Proteases/isolation & purification ; Coronavirus Papain-Like Proteases/metabolism ; Drug Evaluation, Preclinical ; Drug Synergism ; Enzyme Assays ; Flavins/pharmacology ; Fluorescence Resonance Energy Transfer ; Furans/pharmacology ; High-Throughput Screening Assays ; Inhibitory Concentration 50 ; Naphthalenes/pharmacology ; Phenanthrenes/pharmacology ; Quinones/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 ; Vero Cells ; Virus Replication/drug effects
Chemical Substances	2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo(g)pteridine ; 5-amino-2-methyl-N-((R)-1-(1-naphthyl)ethyl)benzamide ; Aniline Compounds ; Antiviral Agents ; Benzamides ; Flavins ; Furans ; Naphthalenes ; Phenanthrenes ; Quinones ; Small Molecule Libraries ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; dihydrotanshinone I (562G9360V6) ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; papain-like protease, SARS-CoV-2 (EC 3.4.22.2) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
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/BCJ20210244
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Article ; Online: Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase.

The Biochemical journal

2021 Volume 478, Issue 13, Page(s) 2481–2497

Abstract: The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral ... ...

Abstract	The COVID-19 pandemic has presented itself as one of the most critical public health challenges of the century, with SARS-CoV-2 being the third member of the Coronaviridae family to cause a fatal disease in humans. There is currently only one antiviral compound, remdesivir, that can be used for the treatment of COVID-19. To identify additional potential therapeutics, we investigated the enzymatic proteins encoded in the SARS-CoV-2 genome. In this study, we focussed on the viral RNA cap methyltransferases, which play key roles in enabling viral protein translation and facilitating viral escape from the immune system. We expressed and purified both the guanine-N7 methyltransferase nsp14, and the nsp16 2'-O-methyltransferase with its activating cofactor, nsp10. We performed an in vitro high-throughput screen for inhibitors of nsp14 using a custom compound library of over 5000 pharmaceutical compounds that have previously been characterised in either clinical or basic research. We identified four compounds as potential inhibitors of nsp14, all of which also showed antiviral capacity in a cell-based model of SARS-CoV-2 infection. Three of the four compounds also exhibited synergistic effects on viral replication with remdesivir.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Chlorobenzenes/pharmacology ; Chlorocebus aethiops ; Drug Evaluation, Preclinical ; Enzyme Assays ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/genetics ; Exoribonucleases/isolation & purification ; Exoribonucleases/metabolism ; Fluorescence Resonance Energy Transfer ; High-Throughput Screening Assays ; Indazoles/pharmacology ; Indenes/pharmacology ; Indoles/pharmacology ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/genetics ; Methyltransferases/isolation & purification ; Methyltransferases/metabolism ; Nitriles/pharmacology ; Phenothiazines/pharmacology ; Purines/pharmacology ; RNA Caps/metabolism ; Reproducibility of Results ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Substrate Specificity ; Trifluperidol/pharmacology ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/isolation & purification ; Viral Nonstructural Proteins/metabolism ; Viral Regulatory and Accessory Proteins/genetics ; Viral Regulatory and Accessory Proteins/isolation & purification ; Viral Regulatory and Accessory Proteins/metabolism
Chemical Substances	Antiviral Agents ; Chlorobenzenes ; Indazoles ; Indenes ; Indoles ; NSP10 protein, SARS-CoV-2 ; NSP16 protein, SARS-CoV-2 ; Nitriles ; Phenothiazines ; Purines ; RNA Caps ; Small Molecule Libraries ; Viral Nonstructural Proteins ; Viral Regulatory and Accessory Proteins ; inauzhin ; (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo(g)indazole-7-carboxylic acid (34ZKU73FU3) ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Methyltransferases (EC 2.1.1.-) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-) ; Alanine (OF5P57N2ZX) ; Trifluperidol (R8869Q7R8I) ; lomeguatrib (S79265T71M)
Language	English
Publishing date	2021-06-07
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/BCJ20210219
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Article ; Online: Long inverted repeat transiently stalls DNA replication by forming hairpin structures on both leading and lagging strands.

Lai, Pey Jiun / Lim, Chew Theng / Le, Hang Phuong / Katayama, Tsutomu / Leach, David R F / Furukohri, Asako / Maki, Hisaji

Genes to cells : devoted to molecular & cellular mechanisms

2016 Volume 21, Issue 2, Page(s) 136–145

Abstract: Long inverted repeats (LIRs), often found in eukaryotic genomes, are unstable in Escherichia coli where they are recognized by the SbcCD (the bacterial Mre11/Rad50 homologue), an endonuclease/exonuclease capable of cleaving hairpin DNA. It has long been ... ...

Abstract	Long inverted repeats (LIRs), often found in eukaryotic genomes, are unstable in Escherichia coli where they are recognized by the SbcCD (the bacterial Mre11/Rad50 homologue), an endonuclease/exonuclease capable of cleaving hairpin DNA. It has long been postulated that LIRs form hairpin structures exclusively on the lagging-strand template during DNA replication, and SbcCD cleaves these hairpin-containing lagging strands to generate DNA double-strand breaks. Using a reconstituted oriC plasmid DNA replication system, we have examined how a replication fork behaves when it meets a LIR on DNA. We have shown that leading-strand synthesis stalls transiently within the upstream half of the LIR. Pausing of lagging-strand synthesis at the LIR was not clearly observed, but the pattern of priming sites for Okazaki fragment synthesis was altered within the downstream half of the LIR. We have found that the LIR on a replicating plasmid was cleaved by SbcCD with almost equal frequency on both the leading- and lagging-strand templates. These data strongly suggest that the LIR is readily converted to a cruciform DNA, before the arrival of the fork, creating SbcCD-sensitive hairpin structures on both leading and lagging strands. We propose a model for the replication-dependent extrusion of LIRs to form cruciform structures that transiently impede replication fork movement.
MeSH term(s)	DNA/metabolism ; DNA Replication ; DNA, Bacterial/chemistry ; DNA, Bacterial/metabolism ; Deoxyribonucleases/metabolism ; Escherichia coli/enzymology ; Escherichia coli/genetics ; Escherichia coli Proteins/metabolism ; Exonucleases/metabolism ; Inverted Repeat Sequences ; Models, Genetic ; Plasmids/genetics
Chemical Substances	DNA, Bacterial ; Escherichia coli Proteins ; Okazaki fragments ; SbcC protein, E coli ; DNA (9007-49-2) ; Deoxyribonucleases (EC 3.1.-) ; Exonucleases (EC 3.1.-) ; sbcD protein, E coli (EC 3.1.-)
Language	English
Publishing date	2016-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1330000-3
ISSN	1365-2443 ; 1356-9597
ISSN (online)	1365-2443
ISSN	1356-9597
DOI	10.1111/gtc.12326
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Article ; Online: Cost-effectiveness modelling of novel oral anticoagulants incorporating real-world elderly patients with atrial fibrillation.

Zhao, Ying Jiao / Lin, Liang / Zhou, Hui Jun / Tan, Keng Teng / Chew, Aik Phon / Foo, Chee Guan / Oh, Chia Theng Daniel / Lim, Boon Peng / Lim, Wee Shiong

International journal of cardiology

2016 Volume 220, Page(s) 794–801

Abstract: Background: Novel oral anticoagulants (NOACs) expand the treatment options for patients with atrial fibrillation (AF). Their benefits need to be weighed against the risk-benefit ratio in real-world elderly patients, prompting this cost-effectiveness ... ...

Abstract	Background: Novel oral anticoagulants (NOACs) expand the treatment options for patients with atrial fibrillation (AF). Their benefits need to be weighed against the risk-benefit ratio in real-world elderly patients, prompting this cost-effectiveness study of NOACs (apixaban, dabigatran, edoxaban and rivaroxaban), warfarin and aspirin for stroke prevention in AF. Methods: Applying effectiveness estimates from a network meta-analysis involving over 800,000 patients from randomised controlled trials and observation studies, our Markov model projected cost and health outcomes for a cohort of 65-year-old AF patients over a life-time. We performed subgroup analysis stratified by age (65-74 and ≥75years), with further analysis limited to observational studies involving dabigatran and rivaroxaban. Results: Compared to warfarin, NOACs (except dabigatran 110) were associated with incremental cost-effectiveness ratios ranging from USD 24,476 to USD 41,448 that were within cost-effectiveness threshold of USD 49,700 (one gross domestic product per capita in Singapore in 2015). Aspirin regimens were dominated. In elderly aged ≥75years, cost effectiveness of NOACs (except apixaban) decreased, owing to worsened performance in safety profile. Analysis limited to observational studies revealed that dabigatran 150 and rivaroxaban were not cost-effective, reflecting increased bleeding risks in non-controlled settings. Threshold analyses revealed that apixaban was no longer cost-effective at two to three times higher bleeding risk. Conclusions: Whilst NOACs are cost-effective in the younger elderly compared to warfarin, their benefits appear to be offset by worsened risk profile in older elderly, especially in non-controlled settings. Decisions on appropriate AF treatment should balance treatment-related benefits, risks, and patient preference.
MeSH term(s)	Administration, Oral ; Aged ; Aged, 80 and over ; Anticoagulants/administration & dosage ; Anticoagulants/economics ; Atrial Fibrillation/drug therapy ; Atrial Fibrillation/economics ; Cost-Benefit Analysis/methods ; Female ; Humans ; Male ; Markov Chains ; Observational Studies as Topic/economics ; Randomized Controlled Trials as Topic/economics
Chemical Substances	Anticoagulants
Language	English
Publishing date	2016-10-01
Publishing country	Netherlands
Document type	Journal Article ; Meta-Analysis
ZDB-ID	779519-1
ISSN	1874-1754 ; 0167-5273
ISSN (online)	1874-1754
ISSN	0167-5273
DOI	10.1016/j.ijcard.2016.06.087
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Article ; Online: Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of nsp5 Main Protease

bioRxiv

Abstract	The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5,000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC50 values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC50. Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC50 in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement.
Keywords	covid19
Language	English
Publishing date	2021-04-08
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.07.438806
Database	COVID19

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