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  1. Article ; Online: Inhibitors of mpox VP39 2'-O methyltransferase efficiently inhibit the monkeypox virus.

    Zgarbová, Michala / Otava, Tomas / Silhan, Jan / Nencka, Radim / Weber, Jan / Boura, Evzen

    Antiviral research

    2023  Volume 218, Page(s) 105714

    Abstract: The RNA 2'-O methyltransferase (MTase) VP39 of the monkeypox virus (MpxV) participates in RNA capping within poxviruses. Sub-micromolar inhibitors targeting this enzyme were already reported. However, these 7-deaza analogs of S-adenosyl methionine (SAH) ... ...

    Abstract The RNA 2'-O methyltransferase (MTase) VP39 of the monkeypox virus (MpxV) participates in RNA capping within poxviruses. Sub-micromolar inhibitors targeting this enzyme were already reported. However, these 7-deaza analogs of S-adenosyl methionine (SAH) had not been tested in cellular assays until now. In this study, we employed plaque assays and cytopathic effect-based assays to evaluate the effectiveness of these compounds. All tested compounds demonstrated antiviral activity against MpxV, with EC
    Language English
    Publishing date 2023-09-09
    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.2023.105714
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1627: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  3. Article ; Online: Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase.

    Silhan, Jan / Klima, Martin / Otava, Tomas / Skvara, Petr / Chalupska, Dominika / Chalupsky, Karel / Kozic, Jan / Nencka, Radim / Boura, Evzen

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 2259

    Abstract: Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the ... ...

    Abstract Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2'-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2'-O-RNA MTase with enzymes from unrelated single-stranded RNA viruses (SARS-CoV-2 and Zika) reveals a conserved sinefungin binding mode, implicating that a single inhibitor could be used against unrelated viral families. Indeed, several of our inhibitors such as TO507 also inhibit the coronaviral nsp14 MTase.
    MeSH term(s) Humans ; Methyltransferases/metabolism ; SARS-CoV-2/genetics ; Monkeypox virus/genetics ; Monkeypox virus/metabolism ; COVID-19 ; Viral Nonstructural Proteins/chemistry ; RNA ; Zika Virus/genetics ; Zika Virus Infection ; RNA, Viral/genetics
    Chemical Substances Methyltransferases (EC 2.1.1.-) ; Viral Nonstructural Proteins ; RNA (63231-63-0) ; RNA, Viral
    Language English
    Publishing date 2023-04-20
    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/s41467-023-38019-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy.

    Dejmek, Milan / Brazdova, Andrea / Otava, Tomáš / Polidarova, Marketa Pimkova / Klíma, Martin / Smola, Miroslav / Vavrina, Zdenek / Buděšínský, Miloš / Dračínský, Martin / Liboska, Radek / Boura, Evzen / Birkuš, Gabriel / Nencka, Radim

    European journal of medicinal chemistry

    2023  Volume 259, Page(s) 115685

    Abstract: Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and cancer. However, cancer ... ...

    Abstract Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and cancer. However, cancer immunotherapy trials with CDNs have shown immune activation, but not complete tumor regression. Nevertheless, we designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast cancer. Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in cancer immunotherapy bridging innate and adaptive immunity.
    MeSH term(s) Animals ; Mice ; Nucleotides, Cyclic/pharmacology ; Nucleotides, Cyclic/metabolism ; DNA ; Neoplasms/drug therapy ; Immunotherapy ; Immunity, Innate
    Chemical Substances Nucleotides, Cyclic ; ADU-S100 (FMW9ZVF53N) ; DNA (9007-49-2)
    Language English
    Publishing date 2023-07-26
    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.2023.115685
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 784: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors.

    Otava, Tomáš / Šála, Michal / Li, Fengling / Fanfrlík, Jindřich / Devkota, Kanchan / Perveen, Sumera / Chau, Irene / Pakarian, Paknoosh / Hobza, Pavel / Vedadi, Masoud / Boura, Evzen / Nencka, Radim

    ACS infectious diseases

    2021  Volume 7, Issue 8, Page(s) 2214–2220

    Abstract: In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases (MTases), nsp14. This MTase catalyzes the transfer of the methyl group ... ...

    Abstract In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases (MTases), nsp14. This MTase catalyzes the transfer of the methyl group from
    MeSH term(s) COVID-19 ; Exoribonucleases ; Humans ; Ligands ; Methyltransferases/genetics ; SARS-CoV-2 ; Viral Nonstructural Proteins
    Chemical Substances Ligands ; Viral Nonstructural Proteins ; Methyltransferases (EC 2.1.1.-) ; Exoribonucleases (EC 3.1.-)
    Language English
    Publishing date 2021-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.1c00131
    Database MEDical Literature Analysis and Retrieval System OnLINE

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