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  1. Article ; Online: A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion.

    Sharma, Jyoti / Du, Ming / Wong, Eric / Mutyam, Venkateshwar / Li, Yao / Chen, Jianguo / Wangen, Jamie / Thrasher, Kari / Fu, Lianwu / Peng, Ning / Tang, Liping / Liu, Kaimao / Mathew, Bini / Bostwick, Robert J / Augelli-Szafran, Corinne E / Bihler, Hermann / Liang, Feng / Mahiou, Jerome / Saltz, Josef /
    Rab, Andras / Hong, Jeong / Sorscher, Eric J / Mendenhall, Eric M / Coppola, Candice J / Keeling, Kim M / Green, Rachel / Mense, Martin / Suto, Mark J / Rowe, Steven M / Bedwell, David M

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 4358

    Abstract: Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation ... ...

    Abstract Premature termination codons (PTCs) prevent translation of a full-length protein and trigger nonsense-mediated mRNA decay (NMD). Nonsense suppression (also termed readthrough) therapy restores protein function by selectively suppressing translation termination at PTCs. Poor efficacy of current readthrough agents prompted us to search for better compounds. An NMD-sensitive NanoLuc readthrough reporter was used to screen 771,345 compounds. Among the 180 compounds identified with readthrough activity, SRI-37240 and its more potent derivative SRI-41315, induce a prolonged pause at stop codons and suppress PTCs associated with cystic fibrosis in immortalized and primary human bronchial epithelial cells, restoring CFTR expression and function. SRI-41315 suppresses PTCs by reducing the abundance of the termination factor eRF1. SRI-41315 also potentiates aminoglycoside-mediated readthrough, leading to synergistic increases in CFTR activity. Combining readthrough agents that target distinct components of the translation machinery is a promising treatment strategy for diseases caused by PTCs.
    MeSH term(s) Aminoglycosides/metabolism ; Codon, Nonsense/antagonists & inhibitors ; Codon, Nonsense/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Genes, Reporter ; Gentamicins/pharmacology ; HEK293 Cells ; Humans ; Microsomes, Liver/drug effects ; Nonsense Mediated mRNA Decay ; Peptide Chain Termination, Translational/drug effects ; Peptide Termination Factors/genetics ; Peptide Termination Factors/metabolism ; Proteasome Endopeptidase Complex/drug effects ; Proteasome Endopeptidase Complex/metabolism ; RNA Interference ; Ribosomes/metabolism ; Structure-Activity Relationship
    Chemical Substances Aminoglycosides ; CFTR protein, human ; Codon, Nonsense ; ETF1 protein, human ; Gentamicins ; Peptide Termination Factors ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6) ; antibiotic G 418 (A08F5XTI6G) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2021-07-16
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-24575-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Identification of Quinolinones as Antivirals against Venezuelan Equine Encephalitis Virus.

    Haese, Nicole N / May, Nicholas A / Taft-Benz, Sharon / Moukha-Chafiq, Omar / Madadi, Nikhil / Zhang, Sixue / Karyakarte, Shuklendu D / Rodzinak, Kevin J / Nguyen, Theresa H / Denton, Michael / Streblow, Aaron D / Towers, Nichole A / Rasmussen, Lynn / Bostwick, Robert J / Maddry, Joseph A / Ananthan, Subramaniam / Augelli-Szafran, Corinne E / Suto, Mark J / Sanders, Wes /
    Moorman, Nathaniel / DeFilippis, Victor / Heise, Mark T / Pathak, Ashish K / Streblow, Daniel N / Morrison, Thomas E

    Antimicrobial agents and chemotherapy

    2021  Volume 65, Issue 9, Page(s) e0024421

    Abstract: Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against ... ...

    Abstract Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. These quinolinones also displayed inhibitory activity against additional alphaviruses, such as Mayaro virus and Ross River virus, although the potency was greatly reduced. Time-of-addition studies indicated that these compounds inhibit the early-to-mid stage of viral replication. Deep sequencing and reverse genetics studies identified two unique resistance mutations in the nsP2 gene (Y102S/C; stalk domain) that conferred VEEV resistance on this chemical series. Moreover, introduction of a K102Y mutation into the nsP2 gene enhanced the sensitivity of chikungunya virus (CHIKV) to this chemical series. Computational modeling of CHIKV and VEEV nsP2 identified a highly probable docking alignment for the quinolinone compounds that require a tyrosine residue at position 102 within the helicase stalk domain. These studies identified a class of compounds with antiviral activity against VEEV and other alphaviruses and provide further evidence that therapeutics targeting nsP2 may be useful against alphavirus infection.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Chikungunya virus ; Encephalitis Virus, Venezuelan Equine/genetics ; Horses ; Humans ; Quinolones/pharmacology ; Virus Replication
    Chemical Substances Antiviral Agents ; Quinolones
    Language English
    Publishing date 2021-08-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 217602-6
    ISSN 1098-6596 ; 0066-4804
    ISSN (online) 1098-6596
    ISSN 0066-4804
    DOI 10.1128/AAC.00244-21
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 809: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  3. Article ; Online: Discovery of a novel inhibitor of kinesin-like protein KIFC1.

    Zhang, Wei / Zhai, Ling / Wang, Yimin / Boohaker, Rebecca J / Lu, Wenyan / Gupta, Vandana V / Padmalayam, Indira / Bostwick, Robert J / White, E Lucile / Ross, Larry J / Maddry, Joseph / Ananthan, Subramaniam / Augelli-Szafran, Corinne E / Suto, Mark J / Xu, Bo / Li, Rongbao / Li, Yonghe

    The Biochemical journal

    2016  Volume 473, Issue 8, Page(s) 1027–1035

    Abstract: Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search ... ...

    Abstract Historically, drugs used in the treatment of cancers also tend to cause damage to healthy cells while affecting cancer cells. Therefore, the identification of novel agents that act specifically against cancer cells remains a high priority in the search for new therapies. In contrast with normal cells, most cancer cells contain multiple centrosomes which are associated with genome instability and tumorigenesis. Cancer cells can avoid multipolar mitosis, which can cause cell death, by clustering the extra centrosomes into two spindle poles, thereby enabling bipolar division. Kinesin-like protein KIFC1 plays a critical role in centrosome clustering in cancer cells, but is not essential for normal cells. Therefore, targeting KIFC1 may provide novel insight into selective killing of cancer cells. In the present study, we identified a small-molecule KIFC1 inhibitor, SR31527, which inhibited microtubule (MT)-stimulated KIFC1 ATPase activity with an IC50 value of 6.6 μM. By using bio layer interferometry technology, we further demonstrated that SR31527 bound directly to KIFC1 with high affinity (Kd=25.4 nM). Our results from computational modelling and saturation-transfer difference (STD)-NMR experiments suggest that SR31527 bound to a novel allosteric site of KIFC1 that appears suitable for developing selective inhibitors of KIFC1. Importantly, SR31527 prevented bipolar clustering of extra centrosomes in triple negative breast cancer (TNBC) cells and significantly reduced TNBC cell colony formation and viability, but was less toxic to normal fibroblasts. Therefore, SR31527 provides a valuable tool for studying the biological function of KIFC1 and serves as a potential lead for the development of novel therapeutic agents for breast cancer treatment.
    MeSH term(s) Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/physiology ; Dose-Response Relationship, Drug ; Drug Discovery/methods ; Humans ; Kinesin/antagonists & inhibitors ; Kinesin/chemistry ; Kinesin/metabolism ; Protein Binding/physiology ; Protein Structure, Secondary ; Thiadiazoles/chemistry ; Thiadiazoles/metabolism ; Thiadiazoles/pharmacology
    Chemical Substances Antineoplastic Agents ; KIFC1 protein, human ; SR31527 ; Thiadiazoles ; Kinesin (EC 3.6.4.4)
    Language English
    Publishing date 2016-02-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BJ20150992
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.110: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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