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Article ; Online: Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin.

Krafcikova, Petra / Silhan, Jan / Nencka, Radim / Boura, Evzen

2020 Volume 11, Issue 1, Page(s) 3717

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2'-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. 2'-O-RNA methyltransferase (MTase) is one of the enzymes of this virus that is a potential target for antiviral therapy as it is crucial for RNA cap formation; an essential process for viral RNA stability. This MTase function is associated with the nsp16 protein, which requires a cofactor, nsp10, for its proper activity. Here we show the crystal structure of the nsp10-nsp16 complex bound to the pan-MTase inhibitor sinefungin in the active site. Our structural comparisons reveal low conservation of the MTase catalytic site between Zika and SARS-CoV-2 viruses, but high conservation of the MTase active site between SARS-CoV-2 and SARS-CoV viruses; these data suggest that the preparation of MTase inhibitors targeting several coronaviruses - but not flaviviruses - should be feasible. Together, our data add to important information for structure-based drug discovery.
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine/metabolism ; Adenosine/pharmacology ; Betacoronavirus/enzymology ; COVID-19 ; Catalytic Domain ; Coronavirus Infections/virology ; Crystallography, X-Ray ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Models, Chemical ; Models, Molecular ; Pandemics ; Pneumonia, Viral/virology ; RNA Caps ; RNA Stability ; RNA, Viral/metabolism ; SARS-CoV-2 ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Viral Regulatory and Accessory Proteins/chemistry ; Viral Regulatory and Accessory Proteins/metabolism
Chemical Substances	Enzyme Inhibitors ; NSP10 protein, SARS-CoV-2 ; NSP16 protein, SARS-CoV-2 ; RNA Caps ; RNA, Viral ; Viral Nonstructural Proteins ; Viral Regulatory and Accessory Proteins ; Methyltransferases (EC 2.1.1.-) ; RNA 2'-O-methyltransferase (EC 2.1.1.-) ; Adenosine (K72T3FS567) ; sinefungin (W2U467CIIL)
Keywords	covid19
Language	English
Publishing date	2020-07-24
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/s41467-020-17495-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Coronaviral RNA-methyltransferases: function, structure and inhibition.

Nencka, Radim / Silhan, Jan / Klima, Martin / Otava, Tomas / Kocek, Hugo / Krafcikova, Petra / Boura, Evzen

Nucleic acids research

2022 Volume 50, Issue 2, Page(s) 635–650

Abstract: Coronaviral methyltransferases (MTases), nsp10/16 and nsp14, catalyze the last two steps of viral RNA-cap creation that takes place in cytoplasm. This cap is essential for the stability of viral RNA and, most importantly, for the evasion of innate immune ...

Abstract	Coronaviral methyltransferases (MTases), nsp10/16 and nsp14, catalyze the last two steps of viral RNA-cap creation that takes place in cytoplasm. This cap is essential for the stability of viral RNA and, most importantly, for the evasion of innate immune system. Non-capped RNA is recognized by innate immunity which leads to its degradation and the activation of antiviral immunity. As a result, both coronaviral MTases are in the center of scientific scrutiny. Recently, X-ray and cryo-EM structures of both enzymes were solved even in complex with other parts of the viral replication complex. High-throughput screening as well as structure-guided inhibitor design have led to the discovery of their potent inhibitors. Here, we critically summarize the tremendous advancement of the coronaviral MTase field since the beginning of COVID pandemic.
MeSH term(s)	Amino Acid Sequence ; Amino Acids/chemistry ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Binding Sites ; Coronavirus/drug effects ; Coronavirus/enzymology ; Coronavirus/genetics ; Drug Discovery ; Humans ; Methylation ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/chemistry ; Methyltransferases/metabolism ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Protein Binding ; RNA, Viral/chemistry ; RNA, Viral/genetics ; RNA, Viral/metabolism ; Structure-Activity Relationship
Chemical Substances	Amino Acids ; Antiviral Agents ; RNA, Viral ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2022-01-06
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/gkab1279
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Article: Putative HIV and SIV G-Quadruplex Sequences in Coding and Noncoding Regions Can Form G-Quadruplexes.

Krafčíková, Petra / Demkovičová, Erika / Halaganová, Andrea / Víglaský, Viktor

Journal of nucleic acids

2017 Volume 2017, Page(s) 6513720

Abstract: The HIV virus is one of the most studied viruses in the world. This is especially true in terms of gene sequencing, and to date more than 9 thousand genomic sequences of HIV isolates have been sequenced and analyzed. In this study, a series of DNA ... ...

Abstract	The HIV virus is one of the most studied viruses in the world. This is especially true in terms of gene sequencing, and to date more than 9 thousand genomic sequences of HIV isolates have been sequenced and analyzed. In this study, a series of DNA sequences, which have the potential to form G-quadruplex structures, is analyzed. Several such sequences were found in various coding and noncoding virus domains, including the U3 LTR, tat, rev, env, and vpx regions. Interestingly, a homological sequence to the already well-known HIV integrase aptamer was identified in the minus-strand. The sequences derived from original isolates were analyzed using standard spectral and electrophoretic methods. In addition, a recently developed methodology is applied which uses induced circular dichroism spectral profiles of G-quadruplex-ligand (Thiazole Orange) complexes to determine if G-rich sequences can adopt G-quadruplex structure. Targeting the G-quadruplexes or peptide domains corresponding to the G-rich coding sequence in HIV offers researchers attractive therapeutic targets which would be of particular use in the development of novel antiviral therapies. The analysis of G-rich regions can provide researchers with a path to find specific targets which could be of interest for specific types of virus.
Language	English
Publishing date	2017-12-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2549000-X
ISSN	2090-021X ; 2090-0201
ISSN (online)	2090-021X
ISSN	2090-0201
DOI	10.1155/2017/6513720
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Article: Ebola virus derived G-quadruplexes: Thiazole orange interaction

Krafčíková, Petra / Erika Demkovičová / Viktor Víglaský

Biochimica et biophysica acta. 2017 May, v. 1861, no. 5

2017

Abstract: The Ebola and Marburg viruses are some of the deadliest viruses in the world. In this study a series of G-rich DNA sequences derived from these types of viruses which possess the potential to form G-quadruplex structures are analyzed. A set of DNA ... ...

Abstract	The Ebola and Marburg viruses are some of the deadliest viruses in the world. In this study a series of G-rich DNA sequences derived from these types of viruses which possess the potential to form G-quadruplex structures are analyzed. A set of DNA oligonucleotides derived from original viral isolates was used as a representative modeling sequence with which to demonstrate the influence of thiazole orange on circular dichroism (CD) spectral profiles. The results show the unique profile of the induced CD (ICD) signal in the visible region caused by interactions between the ligand and G-quadruplexes. This ligand was found to stabilize the G-quadruplex structure and can also induce topological changes and facilitate G-quadruplex multimerization. Thus, the ICD signatures can be used to determine whether specific unknown sequences can form G-quadruplex motifs. The viral sequences were analyzed using standard spectral and electrophoretic methods. In addition, the ability to target G-quadruplexes located in filoviruses offers researchers attractive therapeutic targets which would be of particular use in the development of novel antiviral therapies. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
Keywords	circular dichroism spectroscopy ; DNA ; Ebolavirus ; electrophoresis ; ligands ; models ; nucleotide sequences ; oligonucleotides ; researchers ; thiazoles ; topology ; viruses
Language	English
Dates of publication	2017-05
Size	p. 1321-1328.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	840755-1
ISSN	0304-4165
ISSN	0304-4165
DOI	10.1016/j.bbagen.2016.12.009
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Rational Design of Highly Potent SARS-CoV-2 nsp14 Methyltransferase Inhibitors.

Štefek, Milan / Chalupská, Dominika / Chalupský, Karel / Zgarbová, Michala / Dvořáková, Alexandra / Krafčíková, Petra / Li, Alice Shi Ming / Šála, Michal / Dejmek, Milan / Otava, Tomáš / Chaloupecká, Ema / Kozák, Jaroslav / Kozic, Ján / Vedadi, Masoud / Weber, Jan / Mertlíková-Kaiserová, Helena / Nencka, Radim

ACS omega

2023 Volume 8, Issue 30, Page(s) 27410–27418

Abstract: The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. ... ...

Abstract	The search for new drugs against COVID-19 and its causative agent, SARS-CoV-2, is one of the major trends in the current medicinal chemistry. Targeting capping machinery could be one of the therapeutic concepts based on a unique mechanism of action. Viral RNA cap synthesis involves two methylation steps, the first of which is mediated by the nsp14 protein. Here, we rationally designed and synthesized a series of compounds capable of binding to both the
Language	English
Publishing date	2023-07-21
Publishing country	United States
Document type	Journal Article
ISSN	2470-1343
ISSN (online)	2470-1343
DOI	10.1021/acsomega.3c02815
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Article ; Online: Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin

Petra Krafcikova / Jan Silhan / Radim Nencka / Evzen Boura

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

2020 Volume 7

Abstract: SARS-CoV-2 expresses a 2′-O RNA methyltransferase (MTase) that is involved in the viral RNA cap formation and therefore a target for antiviral therapy. Here the authors provide the structure of nsp10-nsp16 with the panMTase inhibitor sinefungin and ... ...

Abstract	SARS-CoV-2 expresses a 2′-O RNA methyltransferase (MTase) that is involved in the viral RNA cap formation and therefore a target for antiviral therapy. Here the authors provide the structure of nsp10-nsp16 with the panMTase inhibitor sinefungin and report that the development of MTase inhibitor therapies that target multiple coronoaviruses is feasible.
Keywords	Science ; Q ; covid19
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural analysis of the SARS-CoV-2 methyltransferase complex involved in RNA cap creation bound to sinefungin

Petra Krafcikova / Jan Silhan / Radim Nencka / Evzen Boura

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

2020 Volume 7

Abstract	SARS-CoV-2 expresses a 2′-O RNA methyltransferase (MTase) that is involved in the viral RNA cap formation and therefore a target for antiviral therapy. Here the authors provide the structure of nsp10-nsp16 with the panMTase inhibitor sinefungin and report that the development of MTase inhibitor therapies that target multiple coronoaviruses is feasible.
Keywords	Science ; Q
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: G-quadruplex aptamer targeting Protein A and its capability to detect Staphylococcus aureus demonstrated by ELONA.

Stoltenburg, Regina / Krafčiková, Petra / Víglaský, Viktor / Strehlitz, Beate

Scientific reports

2016 Volume 6, Page(s) 33812

Abstract: Aptamers for whole cell detection are selected mostly by the Cell-SELEX procedure. Alternatively, the use of specific cell surface epitopes as target during aptamer selections allows the development of aptamers with ability to bind whole cells. In this ... ...

Abstract	Aptamers for whole cell detection are selected mostly by the Cell-SELEX procedure. Alternatively, the use of specific cell surface epitopes as target during aptamer selections allows the development of aptamers with ability to bind whole cells. In this study, we integrated a formerly selected Protein A-binding aptamer PA#2/8 in an assay format called ELONA (Enzyme-Linked OligoNucleotide Assay) and evaluated the ability of the aptamer to recognise and bind to Staphylococcus aureus presenting Protein A on the cell surface. The full-length aptamer and one of its truncated variants could be demonstrated to specifically bind to Protein A-expressing intact cells of S. aureus, and thus have the potential to expand the portfolio of aptamers that can act as an analytical agent for the specific recognition and rapid detection of the bacterial pathogen. The functionality of the aptamer was found to be based on a very complex, but also highly variable structure. Two structural key elements were identified. The aptamer sequence contains several G-clusters allowing folding into a G-quadruplex structure with the potential of dimeric and multimeric assembly. An inverted repeat able to form an imperfect stem-loop at the 5'-end also contributes essentially to the aptameric function.
MeSH term(s)	Aptamers, Nucleotide/chemistry ; G-Quadruplexes ; Staphylococcal Protein A/analysis ; Staphylococcus aureus
Chemical Substances	Aptamers, Nucleotide ; Staphylococcal Protein A
Language	English
Publishing date	2016-09-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep33812
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Article: Ebola virus derived G-quadruplexes: Thiazole orange interaction.

Krafčíková, Petra / Demkovičová, Erika / Víglaský, Viktor

Biochimica et biophysica acta. General subjects

2016 Volume 1861, Issue 5 Pt B, Page(s) 1321–1328

Abstract	The Ebola and Marburg viruses are some of the deadliest viruses in the world. In this study a series of G-rich DNA sequences derived from these types of viruses which possess the potential to form G-quadruplex structures are analyzed. A set of DNA oligonucleotides derived from original viral isolates was used as a representative modeling sequence with which to demonstrate the influence of thiazole orange on circular dichroism (CD) spectral profiles. The results show the unique profile of the induced CD (ICD) signal in the visible region caused by interactions between the ligand and G-quadruplexes. This ligand was found to stabilize the G-quadruplex structure and can also induce topological changes and facilitate G-quadruplex multimerization. Thus, the ICD signatures can be used to determine whether specific unknown sequences can form G-quadruplex motifs. The viral sequences were analyzed using standard spectral and electrophoretic methods. In addition, the ability to target G-quadruplexes located in filoviruses offers researchers attractive therapeutic targets which would be of particular use in the development of novel antiviral therapies. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
MeSH term(s)	Benzothiazoles/chemistry ; Benzothiazoles/metabolism ; Binding Sites ; Circular Dichroism ; DNA, Viral/chemistry ; DNA, Viral/genetics ; DNA, Viral/metabolism ; Ebolavirus/genetics ; Electrophoresis, Polyacrylamide Gel ; Fluorescent Dyes/chemistry ; Fluorescent Dyes/metabolism ; G-Quadruplexes ; Guanosine/chemistry ; Guanosine/metabolism ; Ligands ; Marburgvirus/genetics ; Nucleic Acid Denaturation ; Oligonucleotides/chemistry ; Oligonucleotides/genetics ; Oligonucleotides/metabolism ; Quinolines/chemistry ; Quinolines/metabolism ; Spectrophotometry, Ultraviolet ; Structure-Activity Relationship ; Temperature
Chemical Substances	Benzothiazoles ; DNA, Viral ; Fluorescent Dyes ; Ligands ; Oligonucleotides ; Quinolines ; thiazole orange (107091-89-4) ; Guanosine (12133JR80S)
Language	English
Publishing date	2016-12-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0304-4165 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0304-4165 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2016.12.009
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Article ; Online: Structural Analysis of the OC43 Coronavirus 2'-O-RNA Methyltransferase.

Dostalik, Pavel / Krafcikova, Petra / Silhan, Jan / Kozic, Jan / Chalupska, Dominika / Chalupsky, Karel / Boura, Evzen

Journal of virology

2021 Volume 95, Issue 15, Page(s) e0046321

Abstract: The OC43 coronavirus is a human pathogen that usually causes only the common cold. One of its key enzymes, similar to other coronaviruses, is the 2'-O-RNA methyltransferase (MTase), which is essential for viral RNA stability and expression. Here, we ... ...

Abstract	The OC43 coronavirus is a human pathogen that usually causes only the common cold. One of its key enzymes, similar to other coronaviruses, is the 2'-O-RNA methyltransferase (MTase), which is essential for viral RNA stability and expression. Here, we report the crystal structure of the 2'-O-RNA MTase in a complex with the pan-methyltransferase inhibitor sinefungin solved at 2.2-Å resolution. The structure reveals an overall fold consistent with the fold observed in other coronaviral MTases. The major differences are in the conformation of the C terminus of the nsp16 subunit and an additional helix in the N terminus of the nsp10 subunits. The structural analysis also revealed very high conservation of the
MeSH term(s)	Betacoronavirus/enzymology ; Betacoronavirus/genetics ; Binding Sites ; Crystallography, X-Ray ; Methyltransferases/chemistry ; Methyltransferases/genetics ; Protein Conformation, alpha-Helical ; Viral Proteins/chemistry ; Viral Proteins/genetics
Chemical Substances	Viral Proteins ; Methyltransferases (EC 2.1.1.-) ; RNA 2'-O-methyltransferase (EC 2.1.1.-)
Language	English
Publishing date	2021-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00463-21
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