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  1. Article ; Online: The combination of levodopa with levodopa-metabolizing enzyme inhibitors prevents severe fever with thrombocytopenia syndrome virus infection in vitro more effectively than single levodopa.

    Ogawa, Motohiko / Murae, Mana / Mizukami, Tomoharu / Gemba, Ryutaro / Irie, Takuya / Shimojima, Masayuki / Ebihara, Hideki / Noguchi, Kohji / Fukasawa, Masayoshi

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy

    2023  Volume 29, Issue 5, Page(s) 549–553

    Abstract: Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that ... ...

    Abstract Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC
    MeSH term(s) Humans ; Levodopa/pharmacology ; Levodopa/therapeutic use ; Carbidopa ; Catechol O-Methyltransferase/metabolism ; Severe Fever with Thrombocytopenia Syndrome/drug therapy ; Catechols/pharmacology ; Catechols/therapeutic use ; Enzyme Inhibitors/therapeutic use ; Phlebovirus
    Chemical Substances Levodopa (46627O600J) ; entacapone (4975G9NM6T) ; Carbidopa (MNX7R8C5VO) ; Catechol O-Methyltransferase (EC 2.1.1.6) ; Catechols ; Enzyme Inhibitors
    Language English
    Publishing date 2023-03-03
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1355399-9
    ISSN 1437-7780 ; 1341-321X
    ISSN (online) 1437-7780
    ISSN 1341-321X
    DOI 10.1016/j.jiac.2023.02.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: SARS-CoV-2 Spike Protein Mutation at Cysteine-488 Impairs Its Golgi Localization and Intracellular S1/S2 Processing.

    Yamamoto, Yuichiro / Inoue, Tetsuya / Inoue, Miyu / Murae, Mana / Fukasawa, Masayoshi / Kaneko, Mika K / Kato, Yukinari / Noguchi, Kohji

    International journal of molecular sciences

    2022  Volume 23, Issue 24

    Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor-angiotensin-converting enzyme-2 (ACE2) as the first step in viral cell entry. SARS-CoV-2 spike protein expression in the ACE2-expressing cell ... ...

    Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor-angiotensin-converting enzyme-2 (ACE2) as the first step in viral cell entry. SARS-CoV-2 spike protein expression in the ACE2-expressing cell surface induces cell-cell membrane fusion, thus forming syncytia. To exert its fusogenic activity, the spike protein is typically processed at a specific site (the S1/S2 site) by cellular proteases such as furin. The C488 residue, located at the spike-ACE2 interacting surface, is critical for the fusogenic and infectious roles of the SARS-CoV-2 spike protein. We have demonstrated that the C488 residue of the spike protein is involved in subcellular targeting and S1/S2 processing. C488 mutant spike localization to the Golgi apparatus and cell surface were impaired. Consequently, the S1/S2 processing of the spike protein, probed by anti-Ser-686-cleaved spike antibody, markedly decreased in C488 mutant spike proteins. Moreover, brefeldin-A-mediated endoplasmic-reticulum-to-Golgi traffic suppression also suppressed spike protein S1/S2 processing. As brefeldin A treatment and C488 mutation inhibited S1/S2 processing and syncytia formation, the C488 residue of spike protein is required for functional spike protein processing.
    Language English
    Publishing date 2022-12-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms232415834
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: L-DOPA, a treatment for Parkinson's disease, and its enantiomer D-DOPA inhibit severe fever with thrombocytopenia syndrome virus infection in vitro.

    Ogawa, Motohiko / Murae, Mana / Gemba, Ryutaro / Irie, Takuya / Shimojima, Masayuki / Saijo, Masayuki / Noguchi, Kohji / Fukasawa, Masayoshi

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy

    2021  Volume 28, Issue 3, Page(s) 373–376

    Abstract: Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of 16.2-47% has been reported. Vaccines and antivirals that are effective against SFTS ... ...

    Abstract Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of 16.2-47% has been reported. Vaccines and antivirals that are effective against SFTS virus (SFTSV) are not yet available in clinical practice. We previously showed that o-dihydroxybenzene is the important chemical core structure for anti-SFTSV activity. In this study, we evaluated the anti-SFTSV efficacy of 3-Hydroxy-L-tyrosine (L-DOPA), a treatment for Parkinson's disease and its enantiomer, 3-hydroxy-D-tyrosine (D-DOPA), both of which have an o-dihydroxybenzene backbone. SFTSV was preincubated with L- or D-DOPA and then inhibition of viral infection as well as viral attachment to host cells were evaluated by viral quantification. Both L- and D-DOPA inhibited SFTSV infection in a dose-dependent manner, mainly by blocking viral attachment to host cells. The half-maximal inhibitory concentration (IC
    MeSH term(s) Bunyaviridae Infections ; Hemorrhagic Fevers, Viral ; Humans ; Levodopa/therapeutic use ; Parkinson Disease/drug therapy ; Phlebovirus ; Severe Fever with Thrombocytopenia Syndrome ; Thrombocytopenia/drug therapy
    Chemical Substances Levodopa (46627O600J)
    Language English
    Publishing date 2021-11-18
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1355399-9
    ISSN 1437-7780 ; 1341-321X
    ISSN (online) 1437-7780
    ISSN 1341-321X
    DOI 10.1016/j.jiac.2021.11.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione

    Murae, Mana / Shimizu, Yoshimi / Yamamoto, Yuichiro / Kobayashi, Asuka / Houri, Masumi / Inoue, Tetsuya / Irie, Takuya / Gemba, Ryutaro / Kondo, Yosuke / Nakano, Yoshio / Miyazaki, Satoru / Yamada, Daisuke / Saitoh, Akiyoshi / Ishii, Isao / Onodera, Taishi / Takahashi, Yoshimasa / Wakita, Takaji / Fukasawa, Masayoshi / Noguchi, Kohji

    Biochemical and biophysical research communications. 2022 Mar. 15, v. 597

    2022  

    Abstract: Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds ... ...

    Abstract Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. Taken together, these data indicate that Cys-488 in spike RBD is required for SARS-CoV-2 spike functions and infectivity, and could be a target of anti-SARS-CoV-2 therapeutics.
    Keywords Severe acute respiratory syndrome coronavirus 2 ; acetylcysteine ; alanine ; cell membranes ; cysteine ; disulfide bonds ; giant cells ; glutathione ; mutation ; pathogenicity ; research ; therapeutics
    Language English
    Dates of publication 2022-0315
    Size p. 30-36.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2022.01.106
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Direct Inhibition of SARS-CoV-2 Spike Protein by Peracetic Acid

    Yuichiro Yamamoto / Yoshio Nakano / Mana Murae / Yoshimi Shimizu / Shota Sakai / Motohiko Ogawa / Tomoharu Mizukami / Tetsuya Inoue / Taishi Onodera / Yoshimasa Takahashi / Takaji Wakita / Masayoshi Fukasawa / Satoru Miyazaki / Kohji Noguchi

    International Journal of Molecular Sciences, Vol 24, Iss 1, p

    2022  Volume 20

    Abstract: Peracetic acid (PAA) disinfectants are effective against a wide range of pathogenic microorganisms, including bacteria, fungi, and viruses. Several studies have shown the efficacy of PAA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ...

    Abstract Peracetic acid (PAA) disinfectants are effective against a wide range of pathogenic microorganisms, including bacteria, fungi, and viruses. Several studies have shown the efficacy of PAA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, its efficacy in SARS-CoV-2 variants and the molecular mechanism of action of PAA against SARS-CoV-2 have not been investigated. SARS-CoV-2 infection depends on the recognition and binding of the cell receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the spike protein. Here, we demonstrated that PAA effectively suppressed pseudotyped virus infection in the Wuhan type and variants, including Delta and Omicron. Similarly, PAA reduced the authentic viral load of SARS-CoV-2. Computational analysis suggested that the hydroxyl radicals produced by PAA cleave the disulfide bridges in the RBD. Additionally, the PAA treatment decreased the abundance of the Wuhan- and variant-type spike proteins. Enzyme-linked immunosorbent assay showed direct inhibition of RBD-ACE2 interactions by PAA. In conclusion, the PAA treatment suppressed SARS-CoV-2 infection, which was dependent on the inhibition of the interaction between the spike RBD and ACE2 by inducing spike protein destabilization. Our findings provide evidence of a potent disinfection strategy against SARS-CoV-2.
    Keywords SARS-CoV-2 ; peracetic acid ; spike protein ; receptor-binding domain ; ACE2 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 612
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione.

    Murae, Mana / Shimizu, Yoshimi / Yamamoto, Yuichiro / Kobayashi, Asuka / Houri, Masumi / Inoue, Tetsuya / Irie, Takuya / Gemba, Ryutaro / Kondo, Yosuke / Nakano, Yoshio / Miyazaki, Satoru / Yamada, Daisuke / Saitoh, Akiyoshi / Ishii, Isao / Onodera, Taishi / Takahashi, Yoshimasa / Wakita, Takaji / Fukasawa, Masayoshi / Noguchi, Kohji

    Biochemical and biophysical research communications

    2022  Volume 597, Page(s) 30–36

    Abstract: Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds ... ...

    Abstract Viral spike proteins play important roles in the viral entry process, facilitating attachment to cellular receptors and fusion of the viral envelope with the cell membrane. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binds to the cellular receptor angiotensin converting enzyme-2 (ACE2) via its receptor-binding domain (RBD). The cysteine residue at position 488, consisting of a disulfide bridge with cysteine 480 is located in an important structural loop at ACE2-binding surface of RBD, and is highly conserved among SARS-related coronaviruses. We showed that the substitution of Cys-488 with alanine impaired pseudotyped SARS-CoV-2 infection, syncytium formation, and cell-cell fusion triggered by SARS-CoV-2 spike expression. Consistently, in vitro binding of RBD and ACE2, spike-mediated cell-cell fusion, and pseudotyped viral infection of VeroE6/TMPRSS2 cells were inhibited by the thiol-reactive compounds N-acetylcysteine (NAC) and a reduced form of glutathione (GSH). Furthermore, we demonstrated that the activity of variant spikes from the SARS-CoV-2 alpha and delta strains were also suppressed by NAC and GSH. Taken together, these data indicate that Cys-488 in spike RBD is required for SARS-CoV-2 spike functions and infectivity, and could be a target of anti-SARS-CoV-2 therapeutics.
    Language English
    Publishing date 2022-01-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 205723-2
    ISSN 1090-2104 ; 0006-291X ; 0006-291X
    ISSN (online) 1090-2104 ; 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2022.01.106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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