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  1. Article ; Online: N

    Ahmed-Belkacem, Rostom / Troussier, Joris / Delpal, Adrien / Canard, Bruno / Vasseur, Jean-Jacques / Decroly, Etienne / Debart, Françoise

    RSC medicinal chemistry

    2024  Volume 15, Issue 3, Page(s) 839–847

    Abstract: RNA cap methylations have been shown to be crucial for the life cycle, replication, and infection of ssRNA viruses, as well as for evading the host's innate immune system. Viral methyltransferases (MTases) therefore represent an attractive target for the ...

    Abstract RNA cap methylations have been shown to be crucial for the life cycle, replication, and infection of ssRNA viruses, as well as for evading the host's innate immune system. Viral methyltransferases (MTases) therefore represent an attractive target for the development of compounds as tools and inhibitors. In coronaviruses,
    Language English
    Publishing date 2024-01-26
    Publishing country England
    Document type Journal Article
    ISSN 2632-8682
    ISSN (online) 2632-8682
    DOI 10.1039/d3md00737e
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: 5'-cap RNA/SAM mimetic conjugates as bisubstrate inhibitors of viral RNA cap 2'-O-methyltransferases.

    Ahmed-Belkacem, Rostom / Sutto-Ortiz, Priscila / Delpal, Adrien / Troussier, Joris / Canard, Bruno / Vasseur, Jean-Jacques / Decroly, Etienne / Debart, Françoise

    Bioorganic chemistry

    2023  Volume 143, Page(s) 107035

    Abstract: Viral RNA cap 2'-O-methyltransferases are considered promising therapeutic targets for antiviral treatments, as they play a key role in the formation of viral RNA cap-1 structures to escape the host immune system. A better understanding of how they ... ...

    Abstract Viral RNA cap 2'-O-methyltransferases are considered promising therapeutic targets for antiviral treatments, as they play a key role in the formation of viral RNA cap-1 structures to escape the host immune system. A better understanding of how they interact with their natural substrates (RNA and the methyl donor SAM) would enable the rational development of potent inhibitors. However, as few structures of 2'-O-MTases in complex with RNA have been described, little is known about substrate recognition by these MTases. For this, chemical tools mimicking the state in which the cap RNA substrate and SAM cofactor are bound in the enzyme's catalytic pocket may prove useful. In this work, we designed and synthesized over 30 RNA conjugates that contain a short oligoribonucleotide (ORN with 4 or 6 nucleotides) with the first nucleotide 2'-O-attached to an adenosine by linkers of different lengths and containing S or N-heteroatoms, or a 1,2,3-triazole ring. These ORN conjugates bearing or not a cap structure at 5'-extremity mimic the methylation transition state with RNA substrate/SAM complex as bisubstrates of 2'-O-MTases. The ORN conjugates were synthesized either by the incorporation of a dinucleoside phosphoramidite during RNA elongation or by click chemistry performed on solid-phase post-RNA elongation. Their ability to inhibit the activity of the nsp16/nsp10 complex of SARS-CoV-2 and the NS5 protein of dengue and Zika viruses was assessed. Significant submicromolar IC
    MeSH term(s) Humans ; Methyltransferases/metabolism ; Methylation ; RNA Caps/chemistry ; RNA Caps/genetics ; RNA Caps/metabolism ; SARS-CoV-2/metabolism ; RNA, Viral ; Zika Virus/metabolism ; Zika Virus Infection
    Chemical Substances Methyltransferases (EC 2.1.1.-) ; RNA Caps ; RNA, Viral
    Language English
    Publishing date 2023-12-30
    Publishing country United States
    Document type Journal Article
    ZDB-ID 120080-x
    ISSN 1090-2120 ; 0045-2068
    ISSN (online) 1090-2120
    ISSN 0045-2068
    DOI 10.1016/j.bioorg.2023.107035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4207: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Potent Inhibition of SARS-CoV-2 nsp14

    Ahmed-Belkacem, Rostom / Hausdorff, Marcel / Delpal, Adrien / Sutto-Ortiz, Priscila / Colmant, Agathe M G / Touret, Franck / Ogando, Natacha S / Snijder, Eric J / Canard, Bruno / Coutard, Bruno / Vasseur, Jean-Jacques / Decroly, Etienne / Debart, Françoise

    Journal of medicinal chemistry

    2022  Volume 65, Issue 8, Page(s) 6231–6249

    Abstract: Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs, and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the design and ... ...

    Abstract Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs, and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the design and synthesis of nucleoside-derived inhibitors against the SARS-CoV-2 nsp14 (
    MeSH term(s) COVID-19/virology ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/chemistry ; Humans ; Methyltransferases ; Molecular Docking Simulation ; RNA, Viral/genetics ; S-Adenosylmethionine ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Sulfonamides/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; COVID-19 Drug Treatment
    Chemical Substances RNA, Viral ; Sulfonamides ; Viral Nonstructural Proteins ; S-Adenosylmethionine (7LP2MPO46S) ; Methyltransferases (EC 2.1.1.-) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-)
    Language English
    Publishing date 2022-04-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.2c00120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MB 1: Show issues

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  4. Article ; Online: Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase.

    Ahmed-Belkacem, Rostom / Sutto-Ortiz, Priscila / Guiraud, Mathis / Canard, Bruno / Vasseur, Jean-Jacques / Decroly, Etienne / Debart, Françoise

    European journal of medicinal chemistry

    2020  Volume 201, Page(s) 112557

    Abstract: The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future ... ...

    Abstract The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7- or 2'O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2'-O-methylation of the cap RNA in order to block viral 2'-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2'-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.
    MeSH term(s) Adenine/chemistry ; Betacoronavirus/isolation & purification ; COVID-19 ; Coronavirus Infections/drug therapy ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/metabolism ; Humans ; Methylation ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/metabolism ; Molecular Docking Simulation ; Nucleosides/chemistry ; Pandemics ; Pneumonia, Viral/drug therapy ; Pneumonia, Viral/metabolism ; Pneumonia, Viral/virology ; RNA Caps/chemistry ; RNA Caps/genetics ; RNA Caps/metabolism ; RNA, Viral/genetics ; RNA, Viral/metabolism ; S-Adenosylmethionine/analogs & derivatives ; S-Adenosylmethionine/pharmacology ; SARS-CoV-2 ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
    Chemical Substances Nucleosides ; RNA Caps ; RNA, Viral ; Viral Nonstructural Proteins ; S-Adenosylmethionine (7LP2MPO46S) ; Methyltransferases (EC 2.1.1.-) ; mRNA (guanine(N7))-methyltransferase (EC 2.1.1.56) ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-) ; Adenine (JAC85A2161)
    Keywords covid19
    Language English
    Publishing date 2020-06-12
    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.2020.112557
    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:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article: Synthesis of adenine dinucleosides SAM analogs as specific inhibitors of SARS-CoV nsp14 RNA cap guanine-N7-methyltransferase

    Ahmed-Belkacem, Rostom / Sutto-Ortiz, Priscila / Guiraud, Mathis / Canard, Bruno / Vasseur, Jean-Jacques / Decroly, Etienne / Debart, Françoise

    Eur J Med Chem

    Abstract: The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future ... ...

    Abstract The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific antiviral inhibitors and/or vaccines to fight these massive outbreaks is an urgent research priority. Enzymes involved in the capping pathway of viruses and more specifically RNA N7- or 2'O-methyltransferases (MTases) are now admitted as potential targets for antiviral chemotherapy. We designed bisubstrate inhibitors by mimicking the transition state of the 2'-O-methylation of the cap RNA in order to block viral 2'-O MTases. This work resulted in the synthesis of 16 adenine dinucleosides with both adenosines connected by various nitrogen-containing linkers. Unexpectedly, all the bisubstrate compounds were barely active against 2'-O MTases of several flaviviruses or SARS-CoV but surprisingly, seven of them showed efficient and specific inhibition against SARS-CoV N7-MTase (nsp14) in the micromolar to submicromolar range. The most active nsp14 inhibitor identified is as potent as but particularly more specific than the broad-spectrum MTase inhibitor, sinefungin. Molecular docking suggests that the inhibitor binds to a pocket formed by the S-adenosyl methionine (SAM) and cap RNA binding sites, conserved among SARS-CoV nsp14. These dinucleoside SAM analogs will serve as starting points for the development of next inhibitors for SARS-CoV-2 nsp14 N7-MTase.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #597389
    Database COVID19

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