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Article ; Online: Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor.

Paul, Debasish / Kales, Stephen C / Cornwell, James A / Afifi, Marwa M / Rai, Ganesha / Zakharov, Alexey / Simeonov, Anton / Cappell, Steven D

Nature communications

2022 Volume 13, Issue 1, Page(s) 6364

Abstract: The F-box protein beta-transducin repeat containing protein (β-TrCP) acts as a substrate adapter for the SCF E3 ubiquitin ligase complex, plays a crucial role in cell physiology, and is often deregulated in many types of cancers. Here, we develop a ... ...

Abstract	The F-box protein beta-transducin repeat containing protein (β-TrCP) acts as a substrate adapter for the SCF E3 ubiquitin ligase complex, plays a crucial role in cell physiology, and is often deregulated in many types of cancers. Here, we develop a fluorescent biosensor to quantitatively measure β-TrCP activity in live, single cells in real-time. We find β-TrCP remains constitutively active throughout the cell cycle and functions to maintain discreet steady-state levels of its substrates. We find no correlation between expression levels of β-TrCP and β-TrCP activity, indicating post-transcriptional regulation. A high throughput screen of small-molecules using our reporter identifies receptor-tyrosine kinase signaling as a key axis for regulating β-TrCP activity by inhibiting binding between β-TrCP and the core SCF complex. Our study introduces a method to monitor β-TrCP activity in live cells and identifies a key signaling network that regulates β-TrCP activity throughout the cell cycle.
MeSH term(s)	beta-Transducin Repeat-Containing Proteins/genetics ; beta-Transducin Repeat-Containing Proteins/metabolism ; F-Box Proteins/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Biosensing Techniques ; Protein-Tyrosine Kinases/metabolism
Chemical Substances	beta-Transducin Repeat-Containing Proteins ; F-Box Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2022-10-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-33762-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor

Debasish Paul / Stephen C. Kales / James A. Cornwell / Marwa M. Afifi / Ganesha Rai / Alexey Zakharov / Anton Simeonov / Steven D. Cappell

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 14

Abstract: β-TrCP plays an important role in diverse cellular processes such as the cell cycle and inflammation. Here the authors develop a biosensor for β-TrCP activity and use it to investigate β-TrCP dynamics during the cell cycle, and to screen a small-molecule ...

Abstract	β-TrCP plays an important role in diverse cellular processes such as the cell cycle and inflammation. Here the authors develop a biosensor for β-TrCP activity and use it to investigate β-TrCP dynamics during the cell cycle, and to screen a small-molecule library for β-TrCP activators and inhibitors.
Keywords	Science ; Q
Language	English
Publishing date	2022-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19.

Shrimp, Jonathan H / Kales, Stephen C / Sanderson, Philip E / Simeonov, Anton / Shen, Min / Hall, Matthew D

ACS pharmacology & translational science

2020 Volume 3, Issue 5, Page(s) 997–1007

Abstract: SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of preclinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host ... ...

Abstract	SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of preclinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host cell would be an effective antiviral strategy. One mechanism for SARS-CoV-2 entry occurs when the spike protein on the surface of SARS-CoV-2 binds to an ACE2 receptor followed by cleavage at two cut sites ("priming") that causes a conformational change allowing for viral and host membrane fusion. TMPRSS2 has an extracellular protease domain capable of cleaving the spike protein to initiate membrane fusion. A validated inhibitor of TMPRSS2 protease activity would be a valuable tool for studying the impact TMPRSS2 has in viral entry and potentially be an effective antiviral therapeutic. To enable inhibitor discovery and profiling of FDA-approved therapeutics, we describe an assay for the biochemical screening of recombinant TMPRSS2 suitable for high throughput application. We demonstrate effectiveness to quantify inhibition down to subnanomolar concentrations by assessing the inhibition of camostat, nafamostat, and gabexate, clinically approved agents in Japan. Also, we profiled a camostat metabolite, FOY-251, and bromhexine hydrochloride, an FDA-approved mucolytic cough suppressant. The rank order potency for the compounds tested are nafamostat (IC
Keywords	covid19
Language	English
Publishing date	2020-09-07
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.0c00106
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19.

Shrimp, Jonathan H / Kales, Stephen C / Sanderson, Philip E / Simeonov, Anton / Shen, Min / Hall, Matthew D

bioRxiv : the preprint server for biology

2020

Abstract: SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of pre-clinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host ... ...

Abstract	SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic. Consequently, much research has gone into the development of pre-clinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host cell would be an effective antiviral strategy. One mechanism for SARS-CoV-2 entry occurs when the spike protein on the surface of SARS-CoV-2 binds to an ACE2 receptor followed by cleavage at two cut sites ("priming") that causes a conformational change allowing for viral and host membrane fusion. TMPRSS2 has an extracellular protease domain capable of cleaving the spike protein to initiate membrane fusion. A validated inhibitor of TMPRSS2 protease activity would be a valuable tool for studying the impact TMPRSS2 has in viral entry and potentially be an effective antiviral therapeutic. To enable inhibitor discovery and profiling of FDA-approved therapeutics, we describe an assay for the biochemical screening of recombinant TMPRSS2 suitable for high throughput application. We demonstrate effectiveness to quantify inhibition down to subnanomolar concentrations by assessing the inhibition of camostat, nafamostat and gabexate, clinically approved agents in Japan. Also, we profiled a camostat metabolite, FOY-251, and bromhexine hydrochloride, an FDA-approved mucolytic cough suppressant. The rank order potency for the compounds tested are: nafamostat (IC
Keywords	covid19
Language	English
Publishing date	2020-08-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.06.23.167544
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Comparative analysis of drug-like EP300/CREBBP acetyltransferase inhibitors.

Crawford, McKenna C / Tripu, Deepika R / Barritt, Samuel A / Jing, Yihang / Gallimore, Diamond / Kales, Stephen C / Bhanu, Natarajan V / Xiong, Ying / Fang, Yuhong / Butler, Kamaria A T / LeClair, Christopher A / Coussens, Nathan P / Simeonov, Anton / Garcia, Benjamin A / Dibble, Christian C / Meier, Jordan L

bioRxiv : the preprint server for biology

2023

Abstract: The human acetyltransferase paralogs EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reported, three unique ...

Abstract	The human acetyltransferase paralogs EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reported, three unique molecular scaffolds have taken precedent: an indane spiro-oxazolidinedione (A-485), a spiro-hydantoin (iP300w), and an aminopyridine (CPI-1612). Despite increasing use of these molecules to study lysine acetylation, the dearth of data regarding their relative biochemical and biological potencies makes their application as chemical probes a challenge. To address this gap, here we present a comparative study of drug-like EP300/CREBBP acetyltransferase inhibitors. First, we determine the biochemical and biological potencies of A-485, iP300w, and CPI-1612, highlighting the increased potency of the latter two compounds at physiological acetyl-CoA concentrations. Cellular evaluation shows that inhibition of histone acetylation and cell growth closely aligns with the biochemical potencies of these molecules, consistent with an on-target mechanism. Finally, we demonstrate the utility of comparative pharmacology by using it to investigate the hypothesis that increased CoA synthesis caused by knockout of PANK4 can competitively antagonize binding of EP300/CREBBP inhibitors and demonstrate proof-of-concept photorelease of a potent inhibitor molecule. Overall, our study demonstrates how knowledge of relative inhibitor potency can guide the study of EP300/CREBBP-dependent mechanisms and suggests new approaches to target delivery, thus broadening the therapeutic window of these preclinical epigenetic drug candidates.
Language	English
Publishing date	2023-05-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.15.540887
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Comparative Analysis of Drug-like EP300/CREBBP Acetyltransferase Inhibitors.

ACS chemical biology

2023 Volume 18, Issue 10, Page(s) 2249–2258

Abstract: The human acetyltransferase paralogues EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reported, three ... ...

Abstract	The human acetyltransferase paralogues EP300 and CREBBP are master regulators of lysine acetylation whose activity has been implicated in various cancers. In the half-decade since the first drug-like inhibitors of these proteins were reported, three unique molecular scaffolds have taken precedent: an indane spiro-oxazolidinedione (A-485), a spiro-hydantoin (iP300w), and an aminopyridine (CPI-1612). Despite increasing use of these molecules to study lysine acetylation, the dearth of data regarding their relative biochemical and biological potencies makes their application as chemical probes a challenge. To address this gap, here we present a comparative study of drug-like EP300/CREBBP acetyltransferase inhibitors. First, we determine the biochemical and biological potencies of A-485, iP300w, and CPI-1612, highlighting the increased potencies of the latter two compounds at physiological acetyl-CoA concentrations. Cellular evaluation shows that inhibition of histone acetylation and cell growth closely aligns with the biochemical potencies of these molecules, consistent with an on-target mechanism. Finally, we demonstrate the utility of comparative pharmacology by using it to investigate the hypothesis that increased CoA synthesis caused by knockout of PANK4 can competitively antagonize the binding of EP300/CREBBP inhibitors and demonstrate proof-of-concept photorelease of a potent inhibitor molecule. Overall, our study demonstrates how knowledge of the relative inhibitor potency can guide the study of EP300/CREBBP-dependent mechanisms and suggests new approaches to target delivery, thus broadening the therapeutic window of these preclinical epigenetic drug candidates.
MeSH term(s)	Humans ; Pharmaceutical Preparations ; Acetyltransferases ; Lysine ; E1A-Associated p300 Protein ; CREB-Binding Protein/chemistry
Chemical Substances	Pharmaceutical Preparations ; Acetyltransferases (EC 2.3.1.-) ; Lysine (K3Z4F929H6) ; E1A-Associated p300 Protein (EC 2.3.1.48) ; CREB-Binding Protein (EC 2.3.1.48) ; EP300 protein, human (EC 2.3.1.48) ; CREBBP protein, human (EC 2.3.1.48)
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00293
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.

Yan, Wenjing / Zhong, Yongwang / Hu, Xin / Xu, Tuan / Zhang, Yinghua / Kales, Stephen / Qu, Yanyan / Talley, Daniel C / Baljinnyam, Bolormaa / LeClair, Christopher A / Simeonov, Anton / Polster, Brian M / Huang, Ruili / Ye, Yihong / Rai, Ganesha / Henderson, Mark J / Tao, Dingyin / Fang, Shengyun

Nature communications

2023 Volume 14, Issue 1, Page(s) 4798

Abstract: UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or ... ...

Abstract	UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1's ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.
MeSH term(s)	Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Auranofin/pharmacology ; Ubiquitination ; Ubiquitin-Activating Enzymes/metabolism
Chemical Substances	Ubiquitin ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Auranofin (3H04W2810V) ; Ubiquitin-Activating Enzymes (EC 6.2.1.45)
Language	English
Publishing date	2023-08-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40537-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19

Shrimp, Jonathan H. / Kales, Stephen C. / Sanderson, Philip E. / Simeonov, Anton / Shen, Min / Hall, Matthew D.

ACS Pharmacology & Translational Science

2020 Volume 3, Issue 5, Page(s) 997–1007

Keywords	covid19
Language	English
Publisher	American Chemical Society (ACS)
Publishing country	us
Document type	Article ; Online
ISSN	2575-9108
DOI	10.1021/acsptsci.0c00106
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immune stimulation of rainbow trout reveals divergent regulation of MH class II-associated invariant chain isoforms.

Semple, Shawna L / Heath, George / Christie, Darah / Braunstein, Marsela / Kales, Stephen C / Dixon, Brian

Immunogenetics

2019 Volume 71, Issue 5-6, Page(s) 407–420

Abstract: Major histocompatibility complex (MHC) class II-associated invariant chain is a chaperone responsible for targeting the MHC class II dimer to the endocytic pathway, thus enabling the loading of exogenous antigens onto the MHC class II receptor. In the ... ...

Abstract	Major histocompatibility complex (MHC) class II-associated invariant chain is a chaperone responsible for targeting the MHC class II dimer to the endocytic pathway, thus enabling the loading of exogenous antigens onto the MHC class II receptor. In the current study, in vivo and in vitro methods were used to investigate the regulation of the rainbow trout invariant chain proteins S25-7 and INVX, upon immune system activation. Whole rainbow trout and the macrophage/monocyte-like cell line RTS11 were treated with PMA at concentrations shown to induce IL-1β transcripts and homotypic aggregation of RTS11. S25-7 transcript levels remained unchanged in the gill, spleen, and liver and were found to be significantly decreased in head kidney beginning 24 h post-stimulation. Meanwhile, INVX transcript levels remained unchanged in all tissues studied. Both S25-7 and INVX proteins were produced in gill and spleen tissues but their expression was unaffected by immune system stimulation. Surprisingly, neither INVX nor S25-7 protein was detected in the secondary immune organ, the head kidney. Analysis of RTS11 cultures demonstrated that both INVX and S25-7 transcript levels significantly increased at 96 h and 120 h following PMA stimulation before returning to control levels at 168 h. Meanwhile, at the protein level in RTS11, S25-7 remained unchanged while INVX had a significant decrease at 168 h post-stimulation. These results indicate that neither INVX nor S25-7 is upregulated upon immune system activation; thus, teleosts have evolved a system of immune regulation that is different than that found in mammals.
MeSH term(s)	Adaptive Immunity ; Animals ; Antigens, Differentiation, B-Lymphocyte/genetics ; Antigens, Differentiation, B-Lymphocyte/immunology ; Gene Expression Profiling ; Gene Expression Regulation ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/immunology ; Immunization ; Immunomodulation/genetics ; Macrophages/immunology ; Macrophages/metabolism ; Monocytes/immunology ; Monocytes/metabolism ; Oncorhynchus mykiss/genetics ; Oncorhynchus mykiss/immunology ; Organ Specificity/genetics ; Organ Specificity/immunology ; Protein Isoforms ; Transcriptome
Chemical Substances	Antigens, Differentiation, B-Lymphocyte ; Histocompatibility Antigens Class II ; Protein Isoforms ; invariant chain
Language	English
Publishing date	2019-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186560-2
ISSN	1432-1211 ; 0093-7711
ISSN (online)	1432-1211
ISSN	0093-7711
DOI	10.1007/s00251-019-01115-y
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Article: A Suite of TMPRSS2 Assays for Screening Drug Repurposing Candidates as Potential Treatments of COVID-19.

Shrimp, Jonathan H / Janiszewski, John / Chen, Catherine Z / Xu, Miao / Wilson, Kelli M / Kales, Stephen C / Sanderson, Philip E / Shinn, Paul / Itkin, Zina / Guo, Hui / Shen, Min / Klumpp-Thomas, Carleen / Michael, Samuel G / Zheng, Wei / Simeonov, Anton / Hall, Matthew D

bioRxiv : the preprint server for biology

2022

Abstract: SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allowed for rapid movement of ... ...

Abstract	SARS-CoV-2 is the causative viral pathogen driving the COVID-19 pandemic that prompted an immediate global response to the development of vaccines and antiviral therapeutics. For antiviral therapeutics, drug repurposing allowed for rapid movement of existing clinical candidates and therapies into human clinical trials to be tested as COVID-19 therapies. One effective antiviral treatment strategy used early in symptom onset is to prevent viral entry. SARS-CoV-2 enters ACE2-expressing cells when the receptor-binding domain of the spike protein on the surface of SARS-CoV-2 binds to ACE2 followed by cleavage at two cut sites on the spike protein. TMPRSS2 has a protease domain capable of cleaving the two cut sites; therefore, a molecule capable of inhibiting the protease activity of TMPRSS2 could be a valuable antiviral therapy. Initially, we used a fluorogenic high-throughput screening assay for the biochemical screening of 6030 compounds in NCATS annotated libraries. Then, we developed an orthogonal biochemical assay that uses mass spectrometry detection of product formation to ensure that hits from the primary screen are not assay artifacts from the fluorescent detection of product formation. Finally, we assessed the hits from the biochemical screening in a cell-based SARS-CoV-2 pseudotyped particle entry assay. Of the six molecules advanced for further studies, two are approved drugs in Japan (camostat and nafamostat), two have entered clinical trials (PCI-27483 and otamixaban), while the other two molecules are peptidomimetic inhibitors of TMPRSS2 taken from the literature that have not advanced into clinical trials (compounds 92 and 114). This work demonstrates a suite of assays for the discovery and development of new inhibitors of TMPRSS2.
Language	English
Publishing date	2022-02-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.02.04.479134
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