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  1. Article ; Online: A method for the efficient evaluation of substrate-based cholinesterase imaging probes for Alzheimer's disease.

    Darvesh, Sultan / Banfield, Scott / Dufour, Maeve / Forrestall, Katrina L / Maillet, Hillary / Reid, G Andrew / Sands, Dane / Pottie, Ian R

    Journal of enzyme inhibition and medicinal chemistry

    2023  Volume 38, Issue 1, Page(s) 2225797

    Abstract: Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes ... ...

    Abstract Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes are typically screened using spectrophotometric methods with pure enzyme for specificity and kinetics. However, the biochemical properties of ChEs associated with AD pathology are altered. The present work was undertaken to determine whether the Karnovsky-Roots (KR) histochemical method could be used to evaluate probes at the site of pathology. Thirty thioesters and esters were synthesised and evaluated using enzyme kinetic and KR methods. Spectrophotometric methods demonstrated all thioesters were ChE substrates, yet only a few provided staining in the brain with the KR method. Esters were ChE substrates with interactions with brain ChEs. These results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.
    MeSH term(s) Humans ; Cholinesterases/metabolism ; Alzheimer Disease/diagnostic imaging ; Cholinesterase Inhibitors/chemistry ; Brain ; Acetylcholinesterase/metabolism
    Chemical Substances Cholinesterases (EC 3.1.1.8) ; Cholinesterase Inhibitors ; 2-(N-cyclohexylamino)ethanesulfonic acid (103-47-9) ; Acetylcholinesterase (EC 3.1.1.7)
    Language English
    Publishing date 2023-06-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 2082578-X
    ISSN 1475-6374 ; 1475-6366
    ISSN (online) 1475-6374
    ISSN 1475-6366
    DOI 10.1080/14756366.2023.2225797
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: 2-Pyridone natural products as inhibitors of SARS-CoV-2 main protease.

    Forrestall, Katrina L / Burley, Darcy E / Cash, Meghan K / Pottie, Ian R / Darvesh, Sultan

    Chemico-biological interactions

    2020  Volume 335, Page(s) 109348

    Abstract: The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease ( ... ...

    Abstract The disease, COVID-19, is caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) for which there is currently no treatment. The SARS-CoV-2 main protease (M
    MeSH term(s) Antiviral Agents/chemistry ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacokinetics ; Biological Products/chemistry ; Biological Products/metabolism ; Biological Products/pharmacokinetics ; Caco-2 Cells ; Catalytic Domain ; Coronavirus 3C Proteases/chemistry ; Coronavirus 3C Proteases/metabolism ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/metabolism ; Cysteine Proteinase Inhibitors/pharmacokinetics ; Humans ; Hydrogen Bonding ; Molecular Docking Simulation ; Molecular Structure ; Protein Binding ; Pyridones/chemistry ; Pyridones/metabolism ; Pyridones/pharmacokinetics ; SARS-CoV-2/enzymology
    Chemical Substances Antiviral Agents ; Biological Products ; Cysteine Proteinase Inhibitors ; Pyridones ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Language English
    Publishing date 2020-12-02
    Publishing country Ireland
    Document type Journal Article
    ZDB-ID 218799-1
    ISSN 1872-7786 ; 0009-2797
    ISSN (online) 1872-7786
    ISSN 0009-2797
    DOI 10.1016/j.cbi.2020.109348
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 686: 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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  3. Article ; Online: Dual inhibition of coronavirus Mpro and PLpro enzymes by phenothiazines and their antiviral activity

    Forrestall, Katrina L. / Pringle, Eric S. / Sands, Dane / Duguay, Brett / Farewell, Brett / Woldemariam, Tekeleselassie / Falzarano, Darryl / Pottie, Ian R. / McCormick, Craig / Darvesh, Sultan

    bioRxiv

    Abstract: Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral ... ...

    Abstract Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (M<sup>pro</sup>) and papain-like protease (PL<sup>pro</sup>), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 M<sup>pro</sup> and PL<sup>pro</sup> protease activity in vitro was identified. In silico docking studies also predicted binding of the phenothiazine to the active sites of M<sup>pro</sup> and PL<sup>pro</sup> from distantly related alphacoronavirus, HCoV-229E (229E) and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cell culture infection models. It was further demonstrated that the compound inhibited 229E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.
    Keywords covid19
    Language English
    Publishing date 2023-09-12
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2023.09.11.557219
    Database COVID19

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