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  1. Article: Targeting NSP16 Methyltransferase for the Broad-Spectrum Clinical Management of Coronaviruses: Managing the Next Pandemic.

    Alshiraihi, Ilham M / Klein, Gerald L / Brown, Mark A

    Diseases (Basel, Switzerland)

    2021  Volume 9, Issue 1

    Abstract: With the approval and distribution of demonstrably safe COVID-19 vaccines bearing exceptionally high efficacy profiles, it may be tempting to envision a return to "normal" in the coming months. However, if there is one lesson to be learned from the ... ...

    Abstract With the approval and distribution of demonstrably safe COVID-19 vaccines bearing exceptionally high efficacy profiles, it may be tempting to envision a return to "normal" in the coming months. However, if there is one lesson to be learned from the ongoing pandemic, it is that, in a world of evolving zoonotic viruses, we must be better prepared for the next deadly outbreak. While the acute nature of the COVID-19 pandemic demanded a highly specific approach, it is advisable to consider the breadth of seemingly endless possibilities in our approach to managing the next inevitable occurrence of an outbreak. Though there is little chance of discovering a "magic pill" to combat all future pathogens, the highly conserved nature of non-surface viral proteins exposes an "Achilles' heel" in the structural genome of viral pathogens. Herein, we consider the potential of targeting such proteins to develop broad-spectrum therapeutics for the future. To illustrate this point, we outline the therapeutic potential of targeting the nonstructural protein 16 methyltransferase, which is conserved across most coronaviruses.
    Language English
    Publishing date 2021-02-01
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2720869-2
    ISSN 2079-9721
    ISSN 2079-9721
    DOI 10.3390/diseases9010012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Spray dried tigecycline dry powder aerosols for the treatment of Nontuberculous mycobacterial pulmonary infections.

    Maloney, Sara E / Alshiraihi, Ilham M / Singh, Amarinder / Stewart, Ian E / Mariner Gonzalez, Jeffrey / Gonzalez-Juarrero, Mercedes / Meibohm, Bernd / Hickey, Anthony J

    Tuberculosis (Edinburgh, Scotland)

    2023  Volume 139, Page(s) 102306

    Abstract: Nontuberculous mycobacterial (NTM) pulmonary infections are a global health concern and a significant contributor to lung disease. Systemic therapies of a cocktail of antibiotics administered over a long period often lead to adverse reactions and/or ... ...

    Abstract Nontuberculous mycobacterial (NTM) pulmonary infections are a global health concern and a significant contributor to lung disease. Systemic therapies of a cocktail of antibiotics administered over a long period often lead to adverse reactions and/or treatment failure. NTM pathogens, such as Mycobacterium abscessus (Mabs), are notoriously difficult to treat due to resistance to many traditional antibiotics. However, the antibiotic tigecycline has demonstrated efficacy in vitro and in vivo against Mabs strains varying in drug susceptibility. Tigecycline exhibits instability in aqueous medium, posing delivery challenges, and has caused severe adverse gastrointestinal effects following intravenous administration, requiring treatment discontinuation. To mitigate both of these concerns, inhalation therapies using dry powder aerosols are proposed as an alternative administration route and means of delivery. Tigecycline dry powder formulations were prepared, characterized, and optimized to develop a therapeutic aerosol with low moisture, high dispersibility, and a large fraction of particles in the respirable size range (1-5 μm). The addition of lactose, leucine, and phosphate buffer salts was investigated to achieve additional stability, dispersibility, and tolerability. Preliminary delivery of the dry powders to Mabs-infected mice for 30 min per day over 7 d demonstrated a 0.91-log (87.7%) decrease in lung bacterial burden.
    MeSH term(s) Animals ; Mice ; Tigecycline ; Powders ; Administration, Inhalation ; Mycobacterium tuberculosis ; Aerosols ; Anti-Bacterial Agents
    Chemical Substances Tigecycline (70JE2N95KR) ; Powders ; Aerosols ; Anti-Bacterial Agents
    Language English
    Publishing date 2023-01-20
    Publishing country Scotland
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2046804-0
    ISSN 1873-281X ; 1472-9792
    ISSN (online) 1873-281X
    ISSN 1472-9792
    DOI 10.1016/j.tube.2023.102306
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Targeting NSP16 Methyltransferase for the Broad-Spectrum Clinical Management of Coronaviruses

    Ilham M. Alshiraihi / Gerald L. Klein / Mark A. Brown

    Diseases, Vol 9, Iss 1, p

    Managing the Next Pandemic

    2021  Volume 12

    Abstract: With the approval and distribution of demonstrably safe COVID-19 vaccines bearing exceptionally high efficacy profiles, it may be tempting to envision a return to “normal” in the coming months. However, if there is one lesson to be learned from the ... ...

    Abstract With the approval and distribution of demonstrably safe COVID-19 vaccines bearing exceptionally high efficacy profiles, it may be tempting to envision a return to “normal” in the coming months. However, if there is one lesson to be learned from the ongoing pandemic, it is that, in a world of evolving zoonotic viruses, we must be better prepared for the next deadly outbreak. While the acute nature of the COVID-19 pandemic demanded a highly specific approach, it is advisable to consider the breadth of seemingly endless possibilities in our approach to managing the next inevitable occurrence of an outbreak. Though there is little chance of discovering a “magic pill” to combat all future pathogens, the highly conserved nature of non-surface viral proteins exposes an “Achilles’ heel” in the structural genome of viral pathogens. Herein, we consider the potential of targeting such proteins to develop broad-spectrum therapeutics for the future. To illustrate this point, we outline the therapeutic potential of targeting the nonstructural protein 16 methyltransferase, which is conserved across most coronaviruses.
    Keywords COVID-19 ; methyltransferase ; coronavirus ; mRNA capping ; Medicine ; R
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells.

    Alshiraihi, Ilham M / Jarrell, Dillon K / Arhouma, Zeyad / Hassell, Kelly N / Montgomery, Jaelyn / Padilla, Alyssa / Ibrahim, Hend M / Crans, Debbie C / Kato, Takamitsu A / Brown, Mark A

    International journal of molecular sciences

    2020  Volume 21, Issue 24

    Abstract: SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns ... ...

    Abstract SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger
    MeSH term(s) Apoptosis/drug effects ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Discovery/methods ; Female ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone-Lysine N-Methyltransferase/antagonists & inhibitors ; Histone-Lysine N-Methyltransferase/chemistry ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Structure-Activity Relationship
    Chemical Substances Histone Deacetylase Inhibitors ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; SMYD3 protein, human (EC 2.1.1.43)
    Language English
    Publishing date 2020-12-15
    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/ijms21249549
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells

    Ilham M. Alshiraihi / Dillon K. Jarrell / Zeyad Arhouma / Kelly N. Hassell / Jaelyn Montgomery / Alyssa Padilla / Hend M. Ibrahim / Debbie C. Crans / Takamitsu A. Kato / Mark A. Brown

    International Journal of Molecular Sciences, Vol 21, Iss 9549, p

    2020  Volume 9549

    Abstract: SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns ... ...

    Abstract SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger ® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer.
    Keywords hit-to-lead ; in silico drug development ; SMYD3 ; methyltransferase ; Inhibitor-4 ; breast cancer ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2020-12-01T00:00:00Z
    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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