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  1. Article ; Online: Dimerization Tendency of 3CLpros of Human Coronaviruses Based on the X-ray Crystal Structure of the Catalytic Domain of SARS-CoV-2 3CLpro

    Seri Jo / Hwa Young Kim / Dong Hae Shin / Mi-Sun Kim

    International Journal of Molecular Sciences, Vol 23, Iss 5268, p

    2022  Volume 5268

    Abstract: 3CLpro of SARS-CoV-2 is a promising target for developing anti-COVID19 agents. In order to evaluate the catalytic activity of 3CLpros according to the presence or absence of the dimerization domain, two forms had been purified and tested. Enzyme kinetic ... ...

    Abstract 3CLpro of SARS-CoV-2 is a promising target for developing anti-COVID19 agents. In order to evaluate the catalytic activity of 3CLpros according to the presence or absence of the dimerization domain, two forms had been purified and tested. Enzyme kinetic studies with a FRET method revealed that the catalytic domain alone presents enzymatic activity, despite it being approximately 8.6 times less than that in the full domain. The catalytic domain was crystallized and its X-ray crystal structure has been determined to 2.3 Å resolution. There are four protomers in the asymmetric unit. Intriguingly, they were packed as a dimer though the dimerization domain was absent. The RMSD of superimposed two catalytic domains was 0.190 for 182 Cα atoms. A part of the long hinge loop (LH-loop) from Gln189 to Asp197 was not built in the model due to its flexibility. The crystal structure indicates that the decreased proteolytic activity of the catalytic domain was due to the incomplete construction of the substrate binding part built by the LH-loop. A structural survey with other 3CLpros showed that SARS-CoV families do not have interactions between DM-loop due to the conformational difference at the last turn of helix α7 compared with others. Therefore, we can conclude that the monomeric form contains nascent enzyme activity and that its efficiency increases by dimerization. This new insight may contribute to understanding the behavior of SARS-CoV-2 3CLpro and thus be useful in developing anti-COVID-19 agents.
    Keywords SARS-CoV-2 3CL protease ; catalytic domain ; X-ray crystallography ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 500
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A Study of 3CLpros as Promising Targets against SARS-CoV and SARS-CoV-2

    Seri Jo / Suwon Kim / Jahyun Yoo / Mi-Sun Kim / Dong Hae Shin

    Microorganisms, Vol 9, Iss 756, p

    2021  Volume 756

    Abstract: The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in serious chaos all over the world. In addition to the available vaccines, the development of treatments to cure COVID- ... ...

    Abstract The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in serious chaos all over the world. In addition to the available vaccines, the development of treatments to cure COVID-19 should be done quickly. One of the fastest strategies is to use a drug-repurposing approach. To provide COVID-19 patients with useful information about medicines currently being used in clinical trials, twenty-four compounds, including antiviral agents, were selected and assayed. These compounds were applied to verify the inhibitory activity for the protein function of 3CLpros (main proteases) of SARS-CoV and SARS-CoV-2. Among them, viral reverse-transcriptase inhibitors abacavir and tenofovir revealed a good inhibitory effect on both 3CLpros. Intriguingly, sildenafil, a cGMP-specific phosphodiesterase type 5 inhibitor also showed significant inhibitory function against them. The in silico docking study suggests that the active-site residues located in the S1 and S2 sites play key roles in the interactions with the inhibitors. The result indicates that 3CLpros are promising targets to cope with SAR-CoV-2 and its variants. The information can be helpful to design treatments to cure patients with COVID-19.
    Keywords SARS-CoV-2 3CL protease ; drug repurposing ; antiviral ; FRET ; inhibitory compounds ; Biology (General) ; QH301-705.5
    Subject code 540
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: A Study of Drug Repurposing to Identify SARS-CoV-2 Main Protease (3CLpro) Inhibitors

    Seri Jo / Luca Signorile / Suwon Kim / Mi-Sun Kim / Oscar Huertas / Raúl Insa / Núria Reig / Dong Hae Shin

    International Journal of Molecular Sciences, Vol 23, Iss 6468, p

    2022  Volume 6468

    Abstract: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wreaked havoc all over the world. Although vaccines for the disease have recently become available and started to be administered ... ...

    Abstract The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wreaked havoc all over the world. Although vaccines for the disease have recently become available and started to be administered to the population in various countries, there is still a strong and urgent need for treatments to cure COVID-19. One of the safest and fastest strategies is represented by drug repurposing (DRPx). In this study, thirty compounds with known safety profiles were identified from a chemical library of Phase II-and-up compounds through a combination of SOM Biotech’s Artificial Intelligence (AI) technology, SOM AI PRO, and in silico docking calculations with third-party software. The selected compounds were then tested in vitro for inhibitory activity against SARS-CoV-2 main protease (3CLpro or Mpro). Of the thirty compounds, three (cynarine, eravacycline, and prexasertib) displayed strong inhibitory activity against SARS-CoV-2 3CLpro. VeroE6 cells infected with SARS-CoV-2 were used to find the cell protection capability of each candidate. Among the three compounds, only eravacycline showed potential antiviral activities with no significant cytotoxicity. A further study is planned for pre-clinical trials.
    Keywords SARS-CoV-2 3CL protease ; drug repurposing ; antiviral ; fret ; inhibitory compounds ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: GTP Preference of d -Glycero-α- d - manno -Heptose-1-Phosphate Guanylyltransferase from Yersinia pseudotuberculosis

    Suwon Kim / Mi-Sun Kim / Seri Jo / Dong Hae Shin

    International Journal of Molecular Sciences, Vol 21, Iss 1, p

    2019  Volume 280

    Abstract: d -glycero-α- d - manno -heptose-1-phosphate guanylyltransferase (HddC) is the fourth enzyme synthesizing a building component of lipopolysaccharide (LPS) of Gram-negative bacteria. Since HddC is a potential new target to develop antibiotics, the ... ...

    Abstract d -glycero-α- d - manno -heptose-1-phosphate guanylyltransferase (HddC) is the fourth enzyme synthesizing a building component of lipopolysaccharide (LPS) of Gram-negative bacteria. Since HddC is a potential new target to develop antibiotics, the analysis of the structural and functional relationship of the complex structure will lead to a better idea to design inhibitory compounds. X-ray crystallography and biochemical experiments to elucidate the guanine preference were performed based on the multiple sequence alignment. The crystal structure of HddC from Yersinia pseudotuberculosis ( YPT ) complexed with guanosine 5′-(β-amino)-diphosphate (GMPPN) has been determined at 1.55 Å resolution. Meanwhile, the mutants revealed their reduced guanine affinity, instead of acquiring noticeable pyrimidine affinity. The complex crystal structure revealed that GMPPN is docked in the catalytic site with the aid of Glu80 positioning on the conserved motif EXXPLGTGGA. In the HddC family, this motif is expected to recruit nucleotides through interacting with bases. The crystal structure shows that oxygen atoms of Glu80 forming two hydrogen bonds play a critical role in interaction with two nitrogen atoms of the guanine base of GMPPN. Interestingly, the binding of GMPPN induced the formation of an oxyanion hole-like conformation on the L(S/A/G)X(S/G) motif and consequently influenced on inducing a conformational shift of the region around Ser55.
    Keywords d -glycero-α- d - manno -heptose-1-phosphate guanylyltransferase (hddc) ; yersinia pseudotuberculosis (ypt) ; guanosine-5′-(β-amino)-diphosphate (gmppn) ; guanine specificity ; antibiotics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Flavonoids with inhibitory activity against SARS-CoV-2 3CLpro

    Seri Jo / Suwon Kim / Dae Yong Kim / Mi-Sun Kim / Dong Hae Shin

    Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 1539-

    2020  Volume 1544

    Abstract: Coronavirus disease 2019 (COVID-19) has been a pandemic disease of which the termination is not yet predictable. Currently, researches to develop vaccines and treatments is going on globally to cope with this disastrous disease. Main protease (3CLpro) ... ...

    Abstract Coronavirus disease 2019 (COVID-19) has been a pandemic disease of which the termination is not yet predictable. Currently, researches to develop vaccines and treatments is going on globally to cope with this disastrous disease. Main protease (3CLpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the good targets to find antiviral agents before vaccines are available. Some flavonoids are known to inhibit 3CLpro from SARS-CoV which causes SARS. Since their sequence identity is 96%, a similar approach was performed with a flavonoid library. Baicalin, herbacetin, and pectolinarin have been discovered to block the proteolytic activity of SARS-CoV-2 3CLpro. An in silico docking study showed that the binding modes of herbacetin and pectolinarin are similar to those obtained from the catalytic domain of SARS-CoV 3CLpro. However, their binding affinities are different due to the usage of whole SARS-CoV-2 3CLpro in this study. Baicalin showed an effective inhibitory activity against SARS-CoV-2 3CLpro and its docking mode is different from those of herbacetin and pectolinarin. This study suggests important scaffolds to design 3CLpro inhibitors to develop antiviral agents or health-foods and dietary supplements to cope with SARS-CoV-2.
    Keywords sars-cov 3cl protease ; antiviral ; flavonoid ; fret ; inhibitory compounds ; Therapeutics. Pharmacology ; RM1-950 ; covid19
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Taylor & Francis Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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