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  1. Article ; Online: Kinetically Controlled Stereoselective Synthesis of 2-Oxo-2-aryl-1,3,2-dioxaphosphorinane Derivatives via a Palladium-Catalyzed Reaction.

    Cui, Hongming / Lin, Daizong / Qun, Dang / Bai, Xu

    The Journal of organic chemistry

    2024  Volume 89, Issue 5, Page(s) 2858–2872

    Abstract: Chiral phosphonate esters have been widely applied in the fields of organic chemistry, medicine, and photoelectric materials. However, it requires the challenging enantioselective synthesis of cyclic phosphonate esters with the desired chiral ... ...

    Abstract Chiral phosphonate esters have been widely applied in the fields of organic chemistry, medicine, and photoelectric materials. However, it requires the challenging enantioselective synthesis of cyclic phosphonate esters with the desired chiral configuration. The two epimers of 2-oxo-2
    Language English
    Publishing date 2024-02-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 123490-0
    ISSN 1520-6904 ; 0022-3263
    ISSN (online) 1520-6904
    ISSN 0022-3263
    DOI 10.1021/acs.joc.3c02151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4473: Show issues Location:
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  2. Article ; Online: X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

    Zhang, Linlin / Lin, Daizong / Sun, Xinyuanyuan / Rox, Katharina / Hilgenfeld, Rolf

    bioRxiv

    Abstract: A novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also ... ...

    Abstract A novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-Å crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.
    Keywords covid19
    Publisher BioRxiv; MedRxiv; WHO
    Document type Article ; Online
    DOI 10.1101/2020.02.17.952879
    Database COVID19

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  3. Article ; Online: X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

    Zhang, Linlin / Lin, Daizong / Sun, Xinyuanyuan / Rox, Katharina / Hilgenfeld, Rolf

    bioRxiv

    Keywords covid19
    Language English
    Publishing date 2020-02-20
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.02.17.952879
    Database COVID19

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  4. Article ; Online: Bioinspired large Stokes shift small molecular dyes for biomedical fluorescence imaging.

    Chen, Hao / Liu, Lingjun / Qian, Kun / Liu, Hailong / Wang, Zhiming / Gao, Feng / Qu, Chunrong / Dai, Wenhao / Lin, Daizong / Chen, Kaixian / Liu, Hong / Cheng, Zhen

    Science advances

    2022  Volume 8, Issue 32, Page(s) eabo3289

    Abstract: Long Stokes shift dyes that minimize cross-talk between the excitation source and fluorescent emission to improve the signal-to-background ratio are highly desired for fluorescence imaging. However, simple small molecular dyes with large Stokes shift ( ... ...

    Abstract Long Stokes shift dyes that minimize cross-talk between the excitation source and fluorescent emission to improve the signal-to-background ratio are highly desired for fluorescence imaging. However, simple small molecular dyes with large Stokes shift (more than 120 nanometers) and near-infrared (NIR) emissions have been rarely reported so far. Here, inspired by the chromophore chemical structure of fluorescent proteins, we designed and synthesized a series of styrene oxazolone dyes (SODs) with simple synthetic methods, which show NIR emissions (>650 nanometers) with long Stokes shift (ranged from 136 to 198 nanometers) and small molecular weight (<450 daltons). The most promising SOD9 shows rapid renal excretion and blood-brain barrier passing properties. After functioning with the mitochondrial-targeted triphenylphosphonium (TPP) group, the resulting SOD9-TPP can be engineered for head-neck tumor imaging, fluorescence image-guided surgery, brain neuroimaging, and on-site pathologic analysis. In summary, our findings add an essential small molecular dye category to the classical dyes.
    Language English
    Publishing date 2022-08-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abo3289
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.

    Zhang, Linlin / Lin, Daizong / Sun, Xinyuanyuan / Curth, Ute / Drosten, Christian / Sauerhering, Lucie / Becker, Stephan / Rox, Katharina / Hilgenfeld, Rolf

    Science (New York, N.Y.)

    2020  Volume 368, Issue 6489, Page(s) 409–412

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease ( ... ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M
    MeSH term(s) Amides/chemistry ; Amides/metabolism ; Amides/pharmacology ; Animals ; Antiviral Agents/chemistry ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Betacoronavirus/drug effects ; Betacoronavirus/enzymology ; Binding Sites ; Cell Line, Tumor ; Coronavirus 3C Proteases ; Crystallography, X-Ray ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Drug Design ; Half-Life ; Humans ; Lung/metabolism ; Mice ; Models, Molecular ; Protease Inhibitors/chemistry ; Protease Inhibitors/metabolism ; Protease Inhibitors/pharmacokinetics ; Protease Inhibitors/pharmacology ; Protein Domains ; Protein Multimerization ; Pyridones/chemistry ; SARS-CoV-2 ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
    Chemical Substances Amides ; Antiviral Agents ; Protease Inhibitors ; Pyridones ; Viral Nonstructural Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Keywords covid19
    Language English
    Publishing date 2020-03-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abb3405
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 27: Show issues Location:
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    Zs.MG 77: Show issues

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  6. Article: [Lead compound optimization strategy (2)--structure optimization strategy for reducing toxicity risks in drug design].

    Liu, Hai-Long / Wang, Jiang / Lin, Dai-Zong / Liu, Hong

    Yao xue xue bao = Acta pharmaceutica Sinica

    2014  Volume 49, Issue 1, Page(s) 1–15

    Abstract: Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure ... ...

    Abstract Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.
    MeSH term(s) Binding Sites ; Cytochrome P-450 Enzyme System/metabolism ; Drug Design ; Drug Discovery/methods ; Drug Recalls ; Drug-Related Side Effects and Adverse Reactions/prevention & control ; Humans ; Structure-Activity Relationship
    Chemical Substances Cytochrome P-450 Enzyme System (9035-51-2)
    Language Chinese
    Publishing date 2014-01
    Publishing country China
    Document type English Abstract ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 788758-9
    ISSN 0513-4870
    ISSN 0513-4870
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 3194: Show issues Location:
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  7. Article ; Online: α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment.

    Zhang, Linlin / Lin, Daizong / Kusov, Yuri / Nian, Yong / Ma, Qingjun / Wang, Jiang / von Brunn, Albrecht / Leyssen, Pieter / Lanko, Kristina / Neyts, Johan / de Wilde, Adriaan / Snijder, Eric J / Liu, Hong / Hilgenfeld, Rolf

    Journal of medicinal chemistry

    2020  Volume 63, Issue 9, Page(s) 4562–4578

    Abstract: The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral ... ...

    Abstract The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic α-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the α-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors,
    MeSH term(s) 3C Viral Proteases ; Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Binding Sites ; Cell Line, Tumor ; Chlorocebus aethiops ; Coronavirus/drug effects ; Coronavirus/enzymology ; Coronavirus 3C Proteases ; Crystallography, X-Ray ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Drug Design ; Enterovirus/drug effects ; Enterovirus/enzymology ; Humans ; Lactams/chemical synthesis ; Lactams/metabolism ; Lactams/pharmacology ; Peptidomimetics/chemical synthesis ; Peptidomimetics/metabolism ; Peptidomimetics/pharmacology ; Protease Inhibitors/chemical synthesis ; Protease Inhibitors/metabolism ; Protease Inhibitors/pharmacology ; Protein Binding ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Viral Proteins/antagonists & inhibitors ; Viral Proteins/chemistry ; Viral Proteins/metabolism ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; Lactams ; Peptidomimetics ; Protease Inhibitors ; Viral Nonstructural Proteins ; Viral Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; 3C Viral Proteases (EC 3.4.22.28) ; Coronavirus 3C Proteases (EC 3.4.22.28)
    Keywords covid19
    Language English
    Publishing date 2020-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.9b01828
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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    Zs.MB 1: Show issues

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  8. Article: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

    Zhang, Linlin / Lin, Daizong / Sun, Xinyuanyuan / Curth, Ute / Drosten, Christian / Sauerhering, Lucie / Becker, Stephan / Rox, Katharina / Hilgenfeld, Rolf

    Science

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #32198291
    Database COVID19

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  9. Article ; Online: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.

    Zhang, Linlin / Lin, Daizong / Sun, Xinyuanyuan / Curth, Ute / Drosten, Christian / Sauerhering, Lucie / Becker, Stephan / Rox, Katharina / Hilgenfeld, Rolf

    368 ; 6489 ; 409 ; 412 ; Science (New York, N.Y.) ; United States

    2020  

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
    Language English
    Publishing date 2020-03-20
    Publisher AAAS
    Publishing country de
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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  10. Article ; Online: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

    Zhang, Linlin / Lin, Daizong / Sun, Xinyuanyuan / Curth, Ute / Drosten, Christian / Sauerhering, Lucie / Becker, Stephan / Rox, Katharina / Hilgenfeld, Rolf

    Science

    2020  Volume 368, Issue 6489, Page(s) 409–412

    Abstract: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M pro , also called 3CL pro ) ... ...

    Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M pro , also called 3CL pro ) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 M pro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M pro . The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
    Keywords Multidisciplinary ; covid19
    Language English
    Publisher American Association for the Advancement of Science (AAAS)
    Publishing country us
    Document type Article ; Online
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abb3405
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 27: Show issues Location:
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    Zs.MG 77: Show issues

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