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  1. Article ; Online: Exploration of 1,2,3-triazolo fused triterpenoids as inhibitors of human coronavirus 229E targeting the viral nsp15 protein.

    Wang, Rui / Stevaert, Annelies / Truong, Tien Nguyen / Li, Qifei / Krasniqi, Besir / Van Loy, Benjamin / Voet, Arnout / Naesens, Lieve / Dehaen, Wim

    Archiv der Pharmazie

    2023  Volume 357, Issue 1, Page(s) e2300442

    Abstract: The coronavirus disease-19 (COVID-19) pandemic has raised major interest in innovative drug concepts to suppress human coronavirus (HCoV) infections. We previously reported on a class of 1,2,3-triazolo fused betulonic acid derivatives causing strong ... ...

    Abstract The coronavirus disease-19 (COVID-19) pandemic has raised major interest in innovative drug concepts to suppress human coronavirus (HCoV) infections. We previously reported on a class of 1,2,3-triazolo fused betulonic acid derivatives causing strong inhibition of HCoV-229E replication via the viral nsp15 protein, which is proposedly related to compound binding at an intermonomer interface in hexameric nsp15. In the present study, we further explored the structure-activity relationship (SAR), by varying the substituent at the 1,2,3-triazolo ring as well as the triterpenoid skeleton. The 1,2,3-triazolo fused triterpenoids were synthesized by a multicomponent triazolization reaction, which has been developed in-house. Several analogs possessing a betulin, oleanolic acid, or ursolic acid core displayed favorable activity and selectivity (EC
    MeSH term(s) Humans ; Coronavirus 229E, Human/metabolism ; Viral Proteins ; Triterpenes/pharmacology ; Structure-Activity Relationship
    Chemical Substances betulonic acid ; Viral Proteins ; Triterpenes
    Language English
    Publishing date 2023-10-15
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 6381-2
    ISSN 1521-4184 ; 0365-6233 ; 1437-1014
    ISSN (online) 1521-4184
    ISSN 0365-6233 ; 1437-1014
    DOI 10.1002/ardp.202300442
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro.

    De Castro, Sonia / Stevaert, Annelies / Maldonado, Miguel / Delpal, Adrien / Vandeput, Julie / Van Loy, Benjamin / Eydoux, Cecilia / Guillemot, Jean-Claude / Decroly, Etienne / Gago, Federico / Canard, Bruno / Camarasa, Maria-Jose / Velázquez, Sonsoles / Naesens, Lieve

    Pharmaceuticals (Basel, Switzerland)

    2022  Volume 15, Issue 8

    Abstract: There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity ...

    Abstract There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2'-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (M
    Language English
    Publishing date 2022-08-18
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph15081021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.

    Stevaert, Annelies / Krasniqi, Besir / Van Loy, Benjamin / Nguyen, Tien / Thomas, Joice / Vandeput, Julie / Jochmans, Dirk / Thiel, Volker / Dijkman, Ronald / Dehaen, Wim / Voet, Arnout / Naesens, Lieve

    Journal of medicinal chemistry

    2021  Volume 64, Issue 9, Page(s) 5632–5644

    Abstract: To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, ... ...

    Abstract To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule
    MeSH term(s) Antiviral Agents/chemical synthesis ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cell Line ; Coronavirus 229E, Human/drug effects ; Coronavirus 229E, Human/enzymology ; Dose-Response Relationship, Drug ; Endoribonucleases/antagonists & inhibitors ; Endoribonucleases/metabolism ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Microbial Sensitivity Tests ; Models, Molecular ; Oleanolic Acid/analogs & derivatives ; Oleanolic Acid/chemical synthesis ; Oleanolic Acid/chemistry ; Oleanolic Acid/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; Enzyme Inhibitors ; Viral Nonstructural Proteins ; betulonic acid ; Oleanolic Acid (6SMK8R7TGJ) ; Endoribonucleases (EC 3.1.-) ; nidoviral uridylate-specific endoribonuclease (EC 3.1.-)
    Language English
    Publishing date 2021-04-20
    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.0c02124
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  4. Article ; Online: Betulonic acid derivatives inhibiting coronavirus replication in cell culture via the nsp15 endoribonuclease

    Krasniqi, Besir / Stevaert, Annelies / Van Loy, Benjamin / Nguyen, Tien / Thomas, Joice / Vandeput, Julie / Jochmans, Dirk / Thiel, Volker / Dijkman, Ronald / Dehaen, Wim / Voet, Arnout / Naesens, Lieve

    bioRxiv

    Abstract: The lack of medication to suppress coronavirus infections is a main reason for the dramatic course of the COVID-19 pandemic. There is an urgent need to identify suitable coronavirus drug targets and corresponding lead molecules. Here we describe the ... ...

    Abstract The lack of medication to suppress coronavirus infections is a main reason for the dramatic course of the COVID-19 pandemic. There is an urgent need to identify suitable coronavirus drug targets and corresponding lead molecules. Here we describe the discovery of a class of coronavirus inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. SAR exploration of these 1,2,3-triazolo fused betulonic acid derivatives yielded lead molecule 5h as a strong inhibitor (antiviral EC<sub>50</sub>: 0.6 μM) of human coronavirus 229E replication. An nsp15 endoribonuclease active site mutant virus was markedly less sensitive to 5h, and selected resistance to the compound mapped to mutations in the N-terminal part of nsp15, at an interface between two nsp15 monomers. The biological findings were substantiated by the nsp15 binding mode for 5h, predicted by docking. Hence, besides delivering a distinct class of inhibitors, our study revealed a druggable pocket in the nsp15 hexamer with relevance for anti-coronavirus drug development.
    Keywords covid19
    Language English
    Publishing date 2020-12-10
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.12.10.418996
    Database COVID19

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