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  1. Article ; Online: From Repurposing to Redesign

    Matthias Göhl / Linlin Zhang / Haifa El Kilani / Xinyuanyuan Sun / Kaixuan Zhang / Mark Brönstrup / Rolf Hilgenfeld

    Molecules, Vol 27, Iss 13, p

    Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease

    2022  Volume 4292

    Abstract: The main protease (M pro ) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M pro . Starting from crystal ... ...

    Abstract The main protease (M pro ) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M pro . Starting from crystal structures of the M pro in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M pro by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, MG-78 , exhibited an IC 50 of 13 nM versus the recombinant M pro , and similar potency was observed for its P1′ N -methyl derivative MG-131 . Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M pro inhibition, we also explored the activity of MG-78 against the M pro of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M pro ), moderate (1.45 µM, Coxsackievirus 3C pro ), and relatively poor (6.7 µM, enterovirus A71 3C pro ), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus M pro s but further optimization would be needed to target enterovirus 3C pro s efficiently.
    Keywords SARS-CoV-2 ; COVID-19 ; main protease ; 3C-like protease ; enterovirus 3C protease ; Coxsackievirus B3 ; Organic chemistry ; QD241-441
    Subject code 333
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Substrate specificity profiling of SARS-CoV-2 Mpro protease provides basis for anti-COVID-19 drug design

    Wioletta Rut / Katarzyna Groborz / Linlin Zhang / Xinyuanyuan Sun / Mikolaj Zmudzinski / Rolf Hilgenfeld / Marcin Drag

    Abstract: AbstractIn December 2019, the first cases of a novel coronavirus infection were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective ...

    Abstract AbstractIn December 2019, the first cases of a novel coronavirus infection were diagnosed in Wuhan, China. Due to international travel and human-to-human transmission, the virus spread rapidly inside and outside of China. Currently, there is no effective antiviral treatment for COVID-19, therefore research efforts are focused on the rapid development of vaccines and antiviral drugs. The SARS-CoV-2 Mpro protease constitutes one of the most attractive antiviral drug targets. To address this emerging problem, we have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 proteases, using natural and a large panel of unnatural amino acids. The results of our work provide a structural framework for the design of inhibitors as antiviral agents or diagnostic tests.
    Keywords covid19
    Publisher biorxiv
    Document type Article ; Online
    DOI 10.1101/2020.03.07.981928
    Database COVID19

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  3. Article ; Online: Ebselen derivatives inhibit SARS-CoV-2 replication by inhibition of its essential proteins

    Mikolaj Zmudzinski / Wioletta Rut / Kamila Olech / Jarosław Granda / Mirosław Giurg / Małgorzata Burda-Grabowska / Rafał Kaleta / Michala Zgarbova / Renata Kasprzyk / Linlin Zhang / Xinyuanyuan Sun / Zongyang Lv / Digant Nayak / Malgorzata Kesik-Brodacka / Shaun K. Olsen / Jan Weber / Rolf Hilgenfeld / Jacek Jemielity / Marcin Drag

    Scientific Reports, Vol 13, Iss 1, Pp 1-

    PLpro and Mpro proteases, and nsp14 guanine N7-methyltransferase

    2023  Volume 16

    Abstract: Abstract Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral ...

    Abstract Abstract Proteases encoded by SARS-CoV-2 constitute a promising target for new therapies against COVID-19. SARS-CoV-2 main protease (Mpro, 3CLpro) and papain-like protease (PLpro) are responsible for viral polyprotein cleavage—a process crucial for viral survival and replication. Recently it was shown that 2-phenylbenzisoselenazol-3(2H)-one (ebselen), an organoselenium anti-inflammatory small-molecule drug, is a potent, covalent inhibitor of both the proteases and its potency was evaluated in enzymatic and antiviral assays. In this study, we screened a collection of 34 ebselen and ebselen diselenide derivatives for SARS-CoV-2 PLpro and Mpro inhibitors. Our studies revealed that ebselen derivatives are potent inhibitors of both the proteases. We identified three PLpro and four Mpro inhibitors superior to ebselen. Independently, ebselen was shown to inhibit the N7-methyltransferase activity of SARS-CoV-2 nsp14 protein involved in viral RNA cap modification. Hence, selected compounds were also evaluated as nsp14 inhibitors. In the second part of our work, we employed 11 ebselen analogues—bis(2-carbamoylaryl)phenyl diselenides—in biological assays to evaluate their anti-SARS-CoV-2 activity in Vero E6 cells. We present their antiviral and cytoprotective activity and also low cytotoxicity. Our work shows that ebselen, its derivatives, and diselenide analogues constitute a promising platform for development of new antivirals targeting the SARS-CoV-2 virus.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication

    Dorothée Bardiot / Laura Vangeel / Mohamed Koukni / Philippe Arzel / Marleen Zwaagstra / Heyrhyoung Lyoo / Patrick Wanningen / Shamshad Ahmad / Linlin Zhang / Xinyuanyuan Sun / Adrien Delpal / Cecilia Eydoux / Jean-Claude Guillemot / Eveline Lescrinier / Hugo Klaassen / Pieter Leyssen / Dirk Jochmans / Karolien Castermans / Rolf Hilgenfeld /
    Colin Robinson / Etienne Decroly / Bruno Canard / Eric J. Snijder / Martijn J. van Hemert / Frank van Kuppeveld / Patrick Chaltin / Johan Neyts / Steven De Jonghe / Arnaud Marchand

    Molecules, Vol 27, Iss 1052, p

    2022  Volume 1052

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experiments demonstrated that it interfered with viral entry. A systematic structure–activity relationship (SAR) study demonstrated that a 3- or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity.
    Keywords COVID-19 ; SARS-CoV-2 ; 1,2,4-oxadiazole ; 1-heteroaryl-2-alkoxyphenyl analogs ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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