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Article ; Online: Structural analysis of the putative SARS-CoV-2 primase complex.

Konkolova, Eva / Klima, Martin / Nencka, Radim / Boura, Evzen

2020 Volume 211, Issue 2, Page(s) 107548

Abstract: We report the crystal structure of the SARS-CoV-2 putative primase composed of the nsp7 and nsp8 proteins. We observed a dimer of dimers (2:2 nsp7-nsp8) in the crystallographic asymmetric unit. The structure revealed a fold with a helical core of the ... ...

Abstract	We report the crystal structure of the SARS-CoV-2 putative primase composed of the nsp7 and nsp8 proteins. We observed a dimer of dimers (2:2 nsp7-nsp8) in the crystallographic asymmetric unit. The structure revealed a fold with a helical core of the heterotetramer formed by both nsp7 and nsp8 that is flanked with two symmetry-related nsp8 β-sheet subdomains. It was also revealed that two hydrophobic interfaces one of approx. 1340 Å
MeSH term(s)	Betacoronavirus/chemistry ; Binding Sites ; Coronavirus RNA-Dependent RNA Polymerase ; Crystallography, X-Ray ; DNA Primase/chemistry ; DNA Primase/metabolism ; Models, Molecular ; Multiprotein Complexes ; Protein Conformation ; Protein Multimerization ; RNA/metabolism ; SARS-CoV-2 ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Multiprotein Complexes ; NS8 protein, SARS-CoV-2 ; Viral Nonstructural Proteins ; RNA (63231-63-0) ; DNA Primase (EC 2.7.7.-) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP7 protein, SARS-CoV-2 (EC 2.7.7.48)
Keywords	covid19
Language	English
Publishing date	2020-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1032718-6
ISSN	1095-8657 ; 1047-8477
ISSN (online)	1095-8657
ISSN	1047-8477
DOI	10.1016/j.jsb.2020.107548
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Article: Structural analysis of the putative SARS-CoV-2 primase complex

Konkolova, Eva / Klima, Martin / Nencka, Radim / Boura, Evzen

J Struct Biol

Abstract	We report the crystal structure of the SARS-CoV-2 putative primase composed of the nsp7 and nsp8 proteins. We observed a dimer of dimers (2:2 nsp7-nsp8) in the crystallographic asymmetric unit. The structure revealed a fold with a helical core of the heterotetramer formed by both nsp7 and nsp8 that is flanked with two symmetry-related nsp8 ß-sheet subdomains. It was also revealed that two hydrophobic interfaces one of approx. 1340 Å2 connects the nsp7 to nsp8 and a second one of approx. 950 Å2 connects the dimers and form the observed heterotetramer. Interestingly, analysis of the surface electrostatic potential revealed a putative RNA binding site that is formed only within the heterotetramer.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #593332
Database	COVID19

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Article ; Online: Structural analysis of the putative SARS-CoV-2 primase complex

Konkolova, Eva / Klima, Martin / Nencka, Radim / Boura, Evzen

Journal of Structural Biology

2020 Volume 211, Issue 2, Page(s) 107548

Keywords	Structural Biology ; covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
ZDB-ID	1032718-6
ISSN	1095-8657 ; 1047-8477
ISSN (online)	1095-8657
ISSN	1047-8477
DOI	10.1016/j.jsb.2020.107548
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Remdesivir triphosphate can efficiently inhibit the RNA-dependent RNA polymerase from various flaviviruses.

Konkolova, Eva / Dejmek, Milan / Hřebabecký, Hubert / Šála, Michal / Böserle, Jiří / Nencka, Radim / Boura, Evzen

Antiviral research

2020 Volume 182, Page(s) 104899

Abstract: Remdesivir was shown to inhibit RNA-dependent RNA-polymerases (RdRp) from distinct viral families such as from Filoviridae (Ebola) and Coronaviridae (SARS-CoV, SARS-CoV-2, MERS). In this study, we tested the ability of remdesivir to inhibit RdRps from ... ...

Abstract	Remdesivir was shown to inhibit RNA-dependent RNA-polymerases (RdRp) from distinct viral families such as from Filoviridae (Ebola) and Coronaviridae (SARS-CoV, SARS-CoV-2, MERS). In this study, we tested the ability of remdesivir to inhibit RdRps from the Flaviviridae family. Instead of remdesivir, we used the active species that is produced in cells from remdesivir, the appropriate triphosphate, which could be directly tested in vitro using recombinant flaviviral polymerases. Our results show that remdesivir can efficiently inhibit RdRps from viruses causing severe illnesses such as Yellow fever, West Nile fever, Japanese and Tick-borne encephalitis, Zika and Dengue. Taken together, this study demonstrates that remdesivir or its derivatives have the potential to become a broad-spectrum antiviral agent effective against many RNA viruses.
MeSH term(s)	Adenosine Triphosphate/analogs & derivatives ; Adenosine Triphosphate/chemistry ; Adenosine Triphosphate/pharmacology ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Betacoronavirus/drug effects ; Betacoronavirus/enzymology ; COVID-19 ; Coronavirus Infections/drug therapy ; Coronavirus Infections/virology ; Flavivirus/drug effects ; Flavivirus/enzymology ; Humans ; Inhibitory Concentration 50 ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/virology ; RNA Viruses/drug effects ; RNA Viruses/enzymology ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; RNA-Dependent RNA Polymerase/metabolism ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Adenosine Triphosphate (8L70Q75FXE) ; GS-441524 triphosphate (AEL0YED4SU) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Keywords	covid19
Language	English
Publishing date	2020-08-05
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.2020.104899
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Article ; Online: Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitor That Blocks SARS-CoV-2 Replication.

Dejmek, Milan / Konkoľová, Eva / Eyer, Luděk / Straková, Petra / Svoboda, Pavel / Šála, Michal / Krejčová, Kateřina / Růžek, Daniel / Boura, Evzen / Nencka, Radim

Viruses

2021 Volume 13, Issue 8

Abstract: SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding ... ...

Abstract	SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.
MeSH term(s)	Adenosine Monophosphate/analogs & derivatives ; Adenosine Monophosphate/pharmacology ; Alanine/analogs & derivatives ; Alanine/pharmacology ; Animals ; Antiviral Agents/pharmacology ; Benzothiazoles/pharmacology ; Cell Line ; Cell Survival/drug effects ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacology ; Humans ; Microbial Sensitivity Tests ; Pyridones/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; SARS-CoV-2/physiology ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Benzothiazoles ; Enzyme Inhibitors ; HeE1-2Tyr ; Pyridones ; remdesivir (3QKI37EEHE) ; Adenosine Monophosphate (415SHH325A) ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; Alanine (OF5P57N2ZX)
Language	English
Publishing date	2021-08-11
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13081585
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Tacrine-Coumarin Derivatives as Topoisomerase Inhibitors with Antitumor Effects on A549 Human Lung Carcinoma Cancer Cell Lines.

Konkoľová, Eva / Hudáčová, Monika / Hamuľaková, Slávka / Jendželovský, Rastislav / Vargová, Jana / Ševc, Juraj / Fedoročko, Peter / Kožurková, Mária

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 4

Abstract: A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores ( ... ...

Abstract	A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives
MeSH term(s)	A549 Cells ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Coumarins/chemistry ; Coumarins/pharmacology ; DNA Topoisomerases, Type I/metabolism ; DNA Topoisomerases, Type II/metabolism ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Poly-ADP-Ribose Binding Proteins/antagonists & inhibitors ; Poly-ADP-Ribose Binding Proteins/metabolism ; Tacrine/chemistry ; Tacrine/pharmacology ; Topoisomerase I Inhibitors/chemistry ; Topoisomerase I Inhibitors/pharmacology ; Topoisomerase II Inhibitors/chemistry ; Topoisomerase II Inhibitors/pharmacology ; Tumor Cells, Cultured
Chemical Substances	Antineoplastic Agents ; Coumarins ; Poly-ADP-Ribose Binding Proteins ; Topoisomerase I Inhibitors ; Topoisomerase II Inhibitors ; Tacrine (4VX7YNB537) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; TOP1 protein, human (EC 5.99.1.2) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; TOP2A protein, human (EC 5.99.1.3)
Language	English
Publishing date	2021-02-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26041133
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Article: Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitor That Blocks SARS-CoV-2 Replication

Dejmek, Milan / Konkoľová, Eva / Eyer, Luděk / Straková, Petra / Svoboda, Pavel / Šála, Michal / Krejčová, Kateřina / Růžek, Daniel / Boura, Evzen / Nencka, Radim

Viruses. 2021 Aug. 11, v. 13, no. 8

2021

Abstract	SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.
Keywords	Flaviviridae ; RNA ; RNA-directed RNA polymerase ; Severe acute respiratory syndrome coronavirus 2 ; antiviral agents ; pandemic
Language	English
Dates of publication	2021-0811
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13081585
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases.

Konkolova, Eva / Krejčová, Kateřina / Eyer, Luděk / Hodek, Jan / Zgarbová, Michala / Fořtová, Andrea / Jirasek, Michael / Teply, Filip / Reyes-Gutierrez, Paul E / Růžek, Daniel / Weber, Jan / Boura, Evzen

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 6

Abstract: Positive-sense single-stranded RNA (+RNA) viruses have proven to be important pathogens that are able to threaten and deeply damage modern societies, as illustrated by the ongoing COVID-19 pandemic. Therefore, compounds active against most or many +RNA ... ...

Abstract	Positive-sense single-stranded RNA (+RNA) viruses have proven to be important pathogens that are able to threaten and deeply damage modern societies, as illustrated by the ongoing COVID-19 pandemic. Therefore, compounds active against most or many +RNA viruses are urgently needed. Here, we present PR673, a helquat-like compound that is able to inhibit the replication of SARS-CoV-2 and tick-borne encephalitis virus in cell culture. Using in vitro polymerase assays, we demonstrate that PR673 inhibits RNA synthesis by viral RNA-dependent RNA polymerases (RdRps). Our results illustrate that the development of broad-spectrum non-nucleoside inhibitors of RdRps is feasible.
MeSH term(s)	COVID-19 ; Encephalitis Viruses, Tick-Borne ; Humans ; Pandemics ; RNA-Dependent RNA Polymerase ; SARS-CoV-2
Chemical Substances	RNA-Dependent RNA Polymerase (EC 2.7.7.48)
Language	English
Publishing date	2022-03-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27061894
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Article: Remdesivir triphosphate can efficiently inhibit the RNA-dependent RNA polymerase from various flaviviruses

Konkolova, Eva / Dejmek, Milan / Hrebabecký, Hubert / Sála, Michal / Böserle, Jirí / Nencka, Radim / Boura, Evzen

Antiviral Res

Abstract	Remdesivir was shown to inhibit RNA-dependent RNA-polymerases (RdRp) from distinct viral families such as from Filoviridae (Ebola) and Coronaviridae (SARS-CoV, SARS-CoV-2, MERS). In this study, we tested the ability of remdesivir to inhibit RdRps from the Flaviviridae family. Instead of remdesivir, we used the active species that is produced in cells from remdesivir, the appropriate triphosphate, which could be directly tested in vitro using recombinant flaviviral polymerases. Our results show that remdesivir can efficiently inhibit RdRps from viruses causing severe illnesses such as Yellow fever, West Nile fever, Japanese and Tick-borne encephalitis, Zika and Dengue. Taken together, this study demonstrates that remdesivir or its derivatives have the potential to become a broad-spectrum antiviral agent effective against many RNA viruses.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #694239
Database	COVID19

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Article: Drug Discovery in Low Data Regimes: Leveraging a Computational Pipeline for the Discovery of Novel SARS-CoV-2 Nsp14-MTase Inhibitors.

Nigam, AkshatKumar / Hurley, Matthew F D / Li, Fengling / Konkoľová, Eva / Klíma, Martin / Trylčová, Jana / Pollice, Robert / Çinaroğlu, Süleyman Selim / Levin-Konigsberg, Roni / Handjaya, Jasemine / Schapira, Matthieu / Chau, Irene / Perveen, Sumera / Ng, Ho-Leung / Ümit Kaniskan, H / Han, Yulin / Singh, Sukrit / Gorgulla, Christoph / Kundaje, Anshul /

Jin, Jian / Voelz, Vincent A / Weber, Jan / Nencka, Radim / Boura, Evzen / Vedadi, Masoud / Aspuru-Guzik, Alán

bioRxiv : the preprint server for biology

2024

Abstract: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. A crucial viral protein, the non-structural protein 14 (nsp14), catalyzes the methylation of viral RNA and plays a critical role in viral genome ...

Abstract	The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has led to significant global morbidity and mortality. A crucial viral protein, the non-structural protein 14 (nsp14), catalyzes the methylation of viral RNA and plays a critical role in viral genome replication and transcription. Due to the low mutation rate in the nsp region among various SARS-CoV-2 variants, nsp14 has emerged as a promising therapeutic target. However, discovering potential inhibitors remains a challenge. In this work, we introduce a computational pipeline for the rapid and efficient identification of potential nsp14 inhibitors by leveraging virtual screening and the NCI open compound collection, which contains 250,000 freely available molecules for researchers worldwide. The introduced pipeline provides a cost-effective and efficient approach for early-stage drug discovery by allowing researchers to evaluate promising molecules without incurring synthesis expenses. Our pipeline successfully identified seven promising candidates after experimentally validating only 40 compounds. Notably, we discovered NSC620333, a compound that exhibits a strong binding affinity to nsp14 with a dissociation constant of 427 ± 84 nM. In addition, we gained new insights into the structure and function of this protein through molecular dynamics simulations. We identified new conformational states of the protein and determined that residues Phe367, Tyr368, and Gln354 within the binding pocket serve as stabilizing residues for novel ligand interactions. We also found that metal coordination complexes are crucial for the overall function of the binding pocket. Lastly, we present the solved crystal structure of the nsp14-MTase complexed with SS148 (PDB:8BWU), a potent inhibitor of methyltransferase activity at the nanomolar level (IC
Language	English
Publishing date	2024-01-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.03.560722
Database	MEDical Literature Analysis and Retrieval System OnLINE

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