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  1. Article ; Online: Drug-Repurposing Screening Identified Tropifexor as a SARS-CoV-2 Papain-like Protease Inhibitor.

    Ma, Chunlong / Hu, Yanmei / Wang, Yuyin / Choza, Juliana / Wang, Jun

    ACS infectious diseases

    2022  Volume 8, Issue 5, Page(s) 1022–1030

    Abstract: The global COVID-19 pandemic underscores the dire need for effective antivirals. Encouraging progress has been made in developing small-molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease ( ... ...

    Abstract The global COVID-19 pandemic underscores the dire need for effective antivirals. Encouraging progress has been made in developing small-molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (M
    MeSH term(s) Antiviral Agents/chemistry ; Benzothiazoles/pharmacology ; Coronavirus Papain-Like Proteases/antagonists & inhibitors ; Drug Repositioning ; Humans ; Isoxazoles/pharmacology ; Pandemics ; SARS-CoV-2/drug effects ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents ; Benzothiazoles ; Isoxazoles ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; papain-like protease, SARS-CoV-2 (EC 3.4.22.2) ; tropifexor (NMZ08KM76Z)
    Language English
    Publishing date 2022-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.1c00629
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays.

    Ma, Chunlong / Tan, Haozhou / Choza, Juliana / Wang, Yuyin / Wang, Jun

    Acta pharmaceutica Sinica. B

    2021  Volume 12, Issue 4, Page(s) 1636–1651

    Abstract: SARS-CoV-2 main protease ( ... ...

    Abstract SARS-CoV-2 main protease (M
    Language English
    Publishing date 2021-11-01
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2211-3835
    ISSN 2211-3835
    DOI 10.1016/j.apsb.2021.10.026
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Drug repurposing screening identified tropifexor as a SARS-CoV-2 papain-like protease inhibitor

    Ma, Chunlong / Wang, Yuyin / Choza, Juliana / Wang, Jun

    bioRxiv

    Abstract: The global COVID-19 pandemic underscores the dire need of effective antivirals. Encouraging progress has been made in developing small molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). However, the ...

    Abstract The global COVID-19 pandemic underscores the dire need of effective antivirals. Encouraging progress has been made in developing small molecule inhibitors targeting the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). However, the development of papain-like protease (PLpro) inhibitors faces several obstacles. Nevertheless, PLpro represents a high-profile drug target given its multifaceted roles in viral replication. PLpro is involved in not only the cleavage of viral polyprotein but also modulation of host immune response. In this study, we conducted a drug-repurposing screening of PLpro against the MedChemExpress bioactive compound library and identified three hits, EACC, KY-226, and tropifexor, as potent PLpro inhibitors with IC50 values ranging from 3.39 to 8.28 micromolar. The three hits showed dose-dependent binding to PLpro in the thermal shift assay. In addition, tropifexor inhibited the cellular PLpro activity in the FlipGFP assay with an IC50 of 10.6 micromolar. Gratifyingly, tropifexor showed antiviral activity against SARS-CoV-2 in Calu-3 cells with an EC50 of 4.03 micromolar, a 7.8-fold increase compared to GRL0617 (EC50 = 31.4 micromolar). Overall, tropifexor represents a novel PLpro inhibitor that can be further developed as SARS-CoV-2 antivirals.
    Keywords covid19
    Language English
    Publishing date 2021-12-03
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.12.02.471030
    Database COVID19

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  4. Article ; Online: Validation and invalidation of SARS-CoV-2 main protease inhibitors using the Flip-GFP and Protease-Glo luciferase assays

    Ma, Chunlong / Tan, Haozhou / Choza, Juliana / Wang, Yuying / Wang, Jun

    bioRxiv

    Abstract: SARS-CoV-2 main protease (Mpro) is one of the most extensive exploited drug targets for COVID-19. Structurally disparate compounds have been reported as Mpro inhibitors, raising the question of their target specificity. To elucidate the target ... ...

    Abstract SARS-CoV-2 main protease (Mpro) is one of the most extensive exploited drug targets for COVID-19. Structurally disparate compounds have been reported as Mpro inhibitors, raising the question of their target specificity. To elucidate the target specificity and the cellular target engagement of the claimed Mpro inhibitors, we systematically characterize their mechanism of action using the cell-free FRET assay, the thermal shift-binding assay, the cell lysate Protease-Glo luciferase assay, and the cell-based Flip-GFP assay. Collectively, our results have shown that majority of the Mpro inhibitors identified from drug repurposing including ebselen, carmofur, disulfiram, and shikonin are promiscuous cysteine inhibitors that are not specific to Mpro, while chloroquine, oxytetracycline, montelukast, candesartan, and dipyridamole do not inhibit Mpro in any of the assays tested. Overall, our study highlights the need of stringent hit validation at the early stage of drug discovery.
    Keywords covid19
    Language English
    Publishing date 2021-08-30
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.08.28.458041
    Database COVID19

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  5. Article: Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity

    Ma, Chunlong / Xia, Zilei / Sacco, Michael Dominic / Hu, Yanmei / Townsend, Julia Alma / Meng, Xiangzhi / Choza, Juliana / Tan, Haozhou / Jang, Janice / Gongora, Maura V. / Zhang, Xiujun / Zhang, Fushun / Xiang, Yan / Marty, Michael Thomas / Chen, Yu / Wang, Jun

    Journal of the American Chemical Society. 2021 Dec. 03, v. 143, no. 49

    2021  

    Abstract: The main protease (Mᵖʳᵒ) is a validated antiviral drug target of SARS-CoV-2. A number of Mᵖʳᵒ inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host ... ...

    Abstract The main protease (Mᵖʳᵒ) is a validated antiviral drug target of SARS-CoV-2. A number of Mᵖʳᵒ inhibitors have now advanced to animal model study and human clinical trials. However, one issue yet to be addressed is the target selectivity over host proteases such as cathepsin L. In this study we describe the rational design of covalent SARS-CoV-2 Mᵖʳᵒ inhibitors with novel cysteine reactive warheads including dichloroacetamide, dibromoacetamide, tribromoacetamide, 2-bromo-2,2-dichloroacetamide, and 2-chloro-2,2-dibromoacetamide. The promising lead candidates Jun9-62-2R (dichloroacetamide) and Jun9-88-6R (tribromoacetamide) had not only potent enzymatic inhibition and antiviral activity but also significantly improved target specificity over caplain and cathepsins. Compared to GC-376, these new compounds did not inhibit the host cysteine proteases including calpain I, cathepsin B, cathepsin K, cathepsin L, and caspase-3. To the best of our knowledge, they are among the most selective covalent Mᵖʳᵒ inhibitors reported thus far. The cocrystal structures of SARS-CoV-2 Mᵖʳᵒ with Jun9-62-2R and Jun9-57-3R reaffirmed our design hypothesis, showing that both compounds form a covalent adduct with the catalytic C145. Overall, these novel compounds represent valuable chemical probes for target validation and drug candidates for further development as SARS-CoV-2 antivirals.
    Keywords Severe acute respiratory syndrome coronavirus 2 ; animal models ; antiviral agents ; antiviral properties ; calpain ; caspase-3 ; cathepsin B ; cathepsin K ; cathepsin L ; cysteine ; enzyme inhibition ; humans
    Language English
    Dates of publication 2021-1203
    Size p. 20697-20709.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/jacs.1c08060
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Discovery of Di- and Trihaloacetamides as Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity.

    Ma, Chunlong / Xia, Zilei / Sacco, Michael Dominic / Hu, Yanmei / Townsend, Julia Alma / Meng, Xiangzhi / Choza, Juliana / Tan, Haozhou / Jang, Janice / Gongora, Maura V / Zhang, Xiujun / Zhang, Fushun / Xiang, Yan / Marty, Michael Thomas / Chen, Yu / Wang, Jun

    Journal of the American Chemical Society

    2021  Volume 143, Issue 49, Page(s) 20697–20709

    Abstract: The main protease ( ... ...

    Abstract The main protease (M
    MeSH term(s) Acetamides/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Cathepsin L/antagonists & inhibitors ; Coronavirus 3C Proteases/antagonists & inhibitors ; Drug Design ; Drug Discovery ; Enzyme Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Protease Inhibitors/pharmacology ; SARS-CoV-2/drug effects ; Structure-Activity Relationship ; Substrate Specificity
    Chemical Substances Acetamides ; Antiviral Agents ; Enzyme Inhibitors ; Protease Inhibitors ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Cathepsin L (EC 3.4.22.15) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2021-12-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/jacs.1c08060
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Bonn / Germany

    Z 4' 55/32: Show issues
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