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Article ; Online: A Fast and Sensitive Method for the Detection of Leuprolide Acetate: A High-Throughput Approach for the In Vitro Evaluation of Liquid Crystal Formulations.

Báez-Santos, Yahira M / Otte, Andrew / Park, Kinam

2016 Volume 88, Issue 9, Page(s) 4613–4618

Abstract: The suitability of using fluorescence spectroscopy to rapidly assay drug release by quantifying the time-dependent increase in total intrinsic protein fluorescence was assessed. Leuprolide acetate, a synthetic nonapeptide analogue of gonadotropin- ... ...

Abstract	The suitability of using fluorescence spectroscopy to rapidly assay drug release by quantifying the time-dependent increase in total intrinsic protein fluorescence was assessed. Leuprolide acetate, a synthetic nonapeptide analogue of gonadotropin-releasing hormone (GnRH or LHRH), is the active pharmaceutical ingredient used to treat a wide range of sex hormone-related disorders, including advanced prostatic cancer, endometriosis, and precocious puberty. During the in vitro evaluation of drug delivery technologies for leuprolide acetate, one of the most time-consuming steps is the detection and accurate quantification of leuprolide release from formulation candidates. Thus far, the dominant means for leuprolide detection involves conventional multistep high-performance liquid chromatography (HPLC) methods, requiring sampling, dilutions, sample filtration, and chromatography, which can take up to 40 min for each sample. With the increasing demand for assay adaptation to high-throughput format, here we sought to exploit fluorescence spectroscopy as a tool to develop a novel method to rapidly assay the in vitro release of leuprolide acetate. By utilizing the intrinsic fluorescence of the tryptophan (Trp) and tyrosine (Tyr) amino acid residues present in the leuprolide nonapeptide, the in vitro release from liquid crystal formulations was accurately quantified as a function of fluorescence intensity. Here, we demonstrate that assaying leuprolide release using intrinsic protein fluorescence in a 96-well format requiring volumes as low as 100 μL is a cost-effective, rapid, and highly sensitive alternative to conventional HPLC methods. Furthermore, the high signal-to-noise ratios and robust Z'-factors of >0.8 indicate high sensitivity, precision, and feasibility for miniaturization, high-throughput format adaptation, and automation.
MeSH term(s)	Chromatography, High Pressure Liquid ; Fluorescence ; High-Throughput Screening Assays/methods ; Leuprolide/analysis ; Liquid Crystals/analysis ; Liquid Crystals/chemistry ; Spectrometry, Fluorescence ; Time Factors
Chemical Substances	Leuprolide (EFY6W0M8TG)
Language	English
Publishing date	2016--03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.6b00190
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Article ; Online: The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds.

Báez-Santos, Yahira M / St John, Sarah E / Mesecar, Andrew D

Antiviral research

2014 Volume 115, Page(s) 21–38

Abstract: Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over ... ...

Abstract	Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses."
MeSH term(s)	Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Coronavirus/enzymology ; Coronavirus/genetics ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Cytokines/metabolism ; Genome, Viral ; Humans ; Models, Molecular ; SARS Virus/drug effects ; SARS Virus/enzymology ; SARS Virus/genetics ; SARS Virus/growth & development ; Ubiquitin/metabolism ; Ubiquitins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/metabolism ; Virus Replication
Chemical Substances	Antiviral Agents ; Cysteine Proteinase Inhibitors ; Cytokines ; Ubiquitin ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0) ; 3C-like proteinase, Coronavirus (EC 3.4.22.-) ; Cysteine Endopeptidases (EC 3.4.22.-)
Keywords	covid19
Language	English
Publishing date	2014-12-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	306628-9
ISSN	1872-9096 ; 0166-3542
ISSN (online)	1872-9096
ISSN	0166-3542
DOI	10.1016/j.antiviral.2014.12.015
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Zs.A 1627: Show issues

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Article ; Online: X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design.

Clasman, Jozlyn R / Báez-Santos, Yahira M / Mettelman, Robert C / O'Brien, Amornrat / Baker, Susan C / Mesecar, Andrew D

Scientific reports

2017 Volume 7, Page(s) 40292

Abstract: Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, ... ...

Abstract	Ubiquitin-like domain 2 (Ubl2) is immediately adjacent to the N-terminus of the papain-like protease (PLpro) domain in coronavirus polyproteins, and it may play a critical role in protease regulation and stability as well as in viral infection. However, our recent cellular studies reveal that removing the Ubl2 domain from MERS PLpro has no effect on its ability to process the viral polyprotein or act as an interferon antagonist, which involves deubiquitinating and deISGylating cellular proteins. Here, we test the hypothesis that the Ubl2 domain is not required for the catalytic function of MERS PLpro in vitro. The X-ray structure of MERS PLpro-∆Ubl2 was determined to 1.9 Å and compared to PLpro containing the N-terminal Ubl2 domain. While the structures were nearly identical, the PLpro-∆Ubl2 enzyme revealed the intact structure of the substrate-binding loop. Moreover, PLpro-∆Ubl2 catalysis against different substrates and a purported inhibitor revealed no differences in catalytic efficiency, substrate specificity, and inhibition. Further, no changes in thermal stability were observed between enzymes. We conclude that the catalytic core of MERS PLpro, i.e. without the Ubl2 domain, is sufficient for catalysis and stability in vitro with utility to evaluate potential inhibitors as a platform for structure-based drug design.
MeSH term(s)	Biosensing Techniques ; Crystallography, X-Ray ; Drug Design ; Enzyme Stability ; Fluorescence Resonance Energy Transfer ; Humans ; Kinetics ; Luciferases/metabolism ; Middle East Respiratory Syndrome Coronavirus/enzymology ; Papain/chemistry ; Polyproteins/chemistry ; Protein Domains ; Protein Processing, Post-Translational ; Temperature ; Ubiquitin/chemistry
Chemical Substances	Polyproteins ; Ubiquitin ; Luciferases (EC 1.13.12.-) ; Papain (EC 3.4.22.2)
Keywords	covid19
Language	English
Publishing date	2017-01-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep40292
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Article ; Online: The in vivo transformation and pharmacokinetic properties of a liquid crystalline drug delivery system.

Otte, Andrew / Báez-Santos, Yahira M / Mun, Ellina A / Soh, Bong-Kwan / Lee, Young-Nam / Park, Kinam

International journal of pharmaceutics

2017 Volume 532, Issue 1, Page(s) 345–351

Abstract: A liquid crystalline (LC) system, composed of phosphatidylcholine, sorbitan monoleate, and tocopherol acetate, was investigated to understand the in vivo transformation after subcutaneous injection, coupled with the physicochemical and pharmacokinetic ... ...

Abstract	A liquid crystalline (LC) system, composed of phosphatidylcholine, sorbitan monoleate, and tocopherol acetate, was investigated to understand the in vivo transformation after subcutaneous injection, coupled with the physicochemical and pharmacokinetic properties of the formulation. The rat model was utilized to monitor a pseudo-time course transformation from a precursor LC formulation to the LC matrix, coupled with the blood concentration profiles of the formulations containing leuprolide acetate. Three formulations that result in the H
Language	English
Publishing date	2017-10-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2017.08.098
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Zs.A 1409: Show issues

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Article ; Online: Catalytic function and substrate specificity of the papain-like protease domain of nsp3 from the Middle East respiratory syndrome coronavirus.

Báez-Santos, Yahira M / Mielech, Anna M / Deng, Xufang / Baker, Susan / Mesecar, Andrew D

Journal of virology

2014 Volume 88, Issue 21, Page(s) 12511–12527

Abstract: Unlabelled: The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N ... ...

Abstract	Unlabelled: The papain-like protease (PLpro) domain from the deadly Middle East respiratory syndrome coronavirus (MERS-CoV) was overexpressed and purified. MERS-CoV PLpro constructs with and without the putative ubiquitin-like (UBL) domain at the N terminus were found to possess protease, deubiquitinating, deISGylating, and interferon antagonism activities in transfected HEK293T cells. The quaternary structure and substrate preferences of MERS-CoV PLpro were determined and compared to those of severe acute respiratory syndrome coronavirus (SARS-CoV) PLpro, revealing prominent differences between these closely related enzymes. Steady-state kinetic analyses of purified MERS-CoV and SARS-CoV PLpros uncovered significant differences in their rates of hydrolysis of 5-aminomethyl coumarin (AMC) from C-terminally labeled peptide, ubiquitin, and ISG15 substrates, as well as in their rates of isopeptide bond cleavage of K48- and K63-linked polyubiquitin chains. MERS-CoV PLpro was found to have 8-fold and 3,500-fold higher catalytic efficiencies for hydrolysis of ISG15-AMC than for hydrolysis of the Ub-AMC and Z-RLRGG-AMC substrates, respectively. A similar trend was observed for SARS-CoV PLpro, although it was much more efficient than MERS-CoV PLpro toward ISG15-AMC and peptide-AMC substrates. MERS-CoV PLpro was found to process K48- and K63-linked polyubiquitin chains at similar rates and with similar debranching patterns, producing monoubiquitin species. However, SARS-CoV PLpro much preferred K48-linked polyubiquitin chains to K63-linked chains, and it rapidly produced di-ubiquitin molecules from K48-linked chains. Finally, potent inhibitors of SARS-CoV PLpro were found to have no effect on MERS-CoV PLpro. A homology model of the MERS-CoV PLpro structure was generated and compared to the X-ray structure of SARS-CoV PLpro to provide plausible explanations for differences in substrate and inhibitor recognition. Importance: Unlocking the secrets of how coronavirus (CoV) papain-like proteases (PLpros) perform their multifunctional roles during viral replication entails a complete mechanistic understanding of their substrate recognition and enzymatic activities. We show that the PLpro domains from the MERS and SARS coronaviruses can recognize and process the same substrates, but with different catalytic efficiencies. The differences in substrate recognition between these closely related PLpros suggest that neither enzyme can be used as a generalized model to explain the kinetic behavior of all CoV PLpros. As a consequence, decoding the mechanisms of PLpro-mediated antagonism of the host innate immune response and the development of anti-CoV PLpro enzyme inhibitors will be a challenging undertaking. The results from this study provide valuable information for understanding how MERS-CoV PLpro-mediated antagonism of the host innate immune response is orchestrated, as well as insight into the design of inhibitors against MERS-CoV PLpro.
MeSH term(s)	Cell Line ; Cloning, Molecular ; Gene Expression ; Humans ; Kinetics ; Middle East Respiratory Syndrome Coronavirus/enzymology ; Middle East Respiratory Syndrome Coronavirus/genetics ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/genetics ; Peptide Hydrolases/metabolism ; Protein Structure, Quaternary ; RNA-Dependent RNA Polymerase/chemistry ; RNA-Dependent RNA Polymerase/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/isolation & purification ; Recombinant Proteins/metabolism ; Substrate Specificity ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Nsp3 protein, Middle East respiratory syndrome coronavirus ; Recombinant Proteins ; Viral Nonstructural Proteins ; Nsp3 protein, SARS-CoV (EC 2.7.7.48) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Peptide Hydrolases (EC 3.4.-)
Keywords	covid19
Language	English
Publishing date	2014-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.01294-14
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Article ; Online: Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating activity of SARS-CoV papain-like protease.

Ratia, Kiira / Kilianski, Andrew / Baez-Santos, Yahira M / Baker, Susan C / Mesecar, Andrew

PLoS pathogens

2014 Volume 10, Issue 5, Page(s) e1004113

Abstract: Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes a papain-like protease (PLpro) with both deubiquitinating (DUB) and deISGylating activities that are proposed to counteract the post-translational modification of signaling molecules that ... ...

Abstract	Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes a papain-like protease (PLpro) with both deubiquitinating (DUB) and deISGylating activities that are proposed to counteract the post-translational modification of signaling molecules that activate the innate immune response. Here we examine the structural basis for PLpro's ubiquitin chain and interferon stimulated gene 15 (ISG15) specificity. We present the X-ray crystal structure of PLpro in complex with ubiquitin-aldehyde and model the interaction of PLpro with other ubiquitin-chain and ISG15 substrates. We show that PLpro greatly prefers K48- to K63-linked ubiquitin chains, and ISG15-based substrates to those that are mono-ubiquitinated. We propose that PLpro's higher affinity for K48-linked ubiquitin chains and ISG15 stems from a bivalent mechanism of binding, where two ubiquitin-like domains prefer to bind in the palm domain of PLpro with the most distal ubiquitin domain interacting with a "ridge" region of the thumb domain. Mutagenesis of residues within this ridge region revealed that these mutants retain viral protease activity and the ability to catalyze hydrolysis of mono-ubiquitin. However, a select number of these mutants have a significantly reduced ability to hydrolyze the substrate ISG15-AMC, or be inhibited by K48-linked diubuiquitin. For these latter residues, we found that PLpro antagonism of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway is abrogated. This identification of key and unique sites in PLpro required for recognition and processing of diubiquitin and ISG15 versus mono-ubiquitin and protease activity provides new insight into ubiquitin-chain and ISG15 recognition and highlights a role for PLpro DUB and deISGylase activity in antagonism of the innate immune response.
MeSH term(s)	Amino Acid Sequence ; Catalytic Domain ; Coronavirus 3C Proteases ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Crystallography, X-Ray ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/genetics ; Cysteine Endopeptidases/metabolism ; Cytokines/metabolism ; HEK293 Cells ; Humans ; Models, Molecular ; Protein Conformation ; Protein Processing, Post-Translational ; SARS Virus/enzymology ; SARS Virus/genetics ; SARS Virus/metabolism ; Substrate Specificity ; Ubiquitin/metabolism ; Ubiquitination/genetics ; Ubiquitins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	Cytokines ; Ubiquitin ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2014-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1004113
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Article ; Online: Formulation and characterization of a liquid crystalline hexagonal mesophase region of phosphatidylcholine, sorbitan monooleate, and tocopherol acetate for sustained delivery of leuprolide acetate.

Báez-Santos, Yahira M / Otte, Andrew / Mun, Ellina A / Soh, Bong-Kwan / Song, Chang-Geun / Lee, Young-Nam / Park, Kinam

International journal of pharmaceutics

2016 Volume 514, Issue 1, Page(s) 314–321

Abstract: Although liquid crystal (LC) systems have been studied before, their utility in drug delivery applications has not been explored in depth. This study examined the development of a 1-month sustained release formulation of leuprolide acetate using an in ... ...

Abstract	Although liquid crystal (LC) systems have been studied before, their utility in drug delivery applications has not been explored in depth. This study examined the development of a 1-month sustained release formulation of leuprolide acetate using an in situ-forming LC matrix. The phase progression upon water absorption was tested through construction of ternary phase diagrams of phosphatidylcholine, sorbitan monooleate, and tocopherol acetate (TA) at increasing water content. Small angle X-ray scattering revealed the presence of lamellar and hexagonal mesophases. The physicochemical characteristics and in vitro drug release were evaluated as a function of the ternary component ratio and its resultant phase behavior. Formulations with increased water uptake capacity displayed greater drug release and enhanced erodability. Removal of TA resulted in increased water uptake capacity and drug release, where 8% (w/w) TA was determined as the critical concentration threshold for divergence of release profiles. In conclusion, characterization of the resultant H
MeSH term(s)	Chemistry, Pharmaceutical/methods ; Delayed-Action Preparations/chemistry ; Drug Delivery Systems/methods ; Drug Liberation ; Hexoses/chemistry ; Leuprolide/chemistry ; Liquid Crystals/chemistry ; Phosphatidylcholines/chemistry ; Scattering, Small Angle ; Water/chemistry ; X-Ray Diffraction/methods ; alpha-Tocopherol/chemistry
Chemical Substances	Delayed-Action Preparations ; Hexoses ; Phosphatidylcholines ; Water (059QF0KO0R) ; sorbitan monooleate (06XEA2VD56) ; Leuprolide (EFY6W0M8TG) ; alpha-Tocopherol (H4N855PNZ1)
Language	English
Publishing date	2016-11-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	428962-6
ISSN	1873-3476 ; 0378-5173
ISSN (online)	1873-3476
ISSN	0378-5173
DOI	10.1016/j.ijpharm.2016.06.138
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Zs.A 1409: Show issues

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Article ; Online: MERS-CoV papain-like protease has deISGylating and deubiquitinating activities.

Mielech, Anna M / Kilianski, Andy / Baez-Santos, Yahira M / Mesecar, Andrew D / Baker, Susan C

Virology

2013 Volume 450-451, Page(s) 64–70

Abstract: Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate ... ...

Abstract	Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate immune response to infection. Here, we investigate the predicted DUB activity of the PLpro domain of the recently described Middle East Respiratory Syndrome Coronavirus (MERS-CoV). We found that expression of MERS-CoV PLpro reduces the levels of ubiquitinated and ISGylated host cell proteins; consistent with multifunctional PLpro activity. Further, we compared the ability of MERS-CoV PLpro and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) PLpro to block innate immune signaling of proinflammatory cytokines. We show that expression of SARS-CoV and MERS-CoV PLpros blocks upregulation of cytokines CCL5, IFN-β and CXCL10 in stimulated cells. Overall these results indicate that the PLpro domains of MERS-CoV and SARS-CoV have the potential to modify the innate immune response to viral infection and contribute to viral pathogenesis.
MeSH term(s)	Amino Acid Sequence ; Cell Line ; Coronaviridae/chemistry ; Coronaviridae/enzymology ; Coronaviridae/genetics ; Coronaviridae Infections/genetics ; Coronaviridae Infections/metabolism ; Coronaviridae Infections/virology ; Cytokines/genetics ; Cytokines/metabolism ; Glycosylation ; Humans ; Molecular Sequence Data ; Papain/chemistry ; Papain/genetics ; Papain/metabolism ; Protein Structure, Tertiary ; SARS Virus/enzymology ; SARS Virus/genetics ; Ubiquitination ; Ubiquitins/genetics ; Ubiquitins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/genetics ; Viral Proteins/metabolism
Chemical Substances	Cytokines ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0) ; Papain (EC 3.4.22.2)
Keywords	covid19
Language	English
Publishing date	2013-12-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2013.11.040
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Article: MERS-CoV papain-like protease has deISGylating and deubiquitinating activities

Mielech, Anna M / Kilianski, Andy / Baez-Santos, Yahira M / Mesecar, Andrew D / Baker, Susan C

Virology. 2014 Feb., v. 450-451

2014

Abstract	Coronaviruses encode papain-like proteases (PLpro) that are often multifunctional enzymes with protease activity to process the viral replicase polyprotein and deubiquitinating (DUB)/deISGylating activity, which is hypothesized to modify the innate immune response to infection. Here, we investigate the predicted DUB activity of the PLpro domain of the recently described Middle East Respiratory Syndrome Coronavirus (MERS-CoV). We found that expression of MERS-CoV PLpro reduces the levels of ubiquitinated and ISGylated host cell proteins; consistent with multifunctional PLpro activity. Further, we compared the ability of MERS-CoV PLpro and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) PLpro to block innate immune signaling of proinflammatory cytokines. We show that expression of SARS-CoV and MERS-CoV PLpros blocks upregulation of cytokines CCL5, IFN-β and CXCL10 in stimulated cells. Overall these results indicate that the PLpro domains of MERS-CoV and SARS-CoV have the potential to modify the innate immune response to viral infection and contribute to viral pathogenesis.
Keywords	Coronavirus infections ; Middle East respiratory syndrome coronavirus ; Severe acute respiratory syndrome coronavirus ; chemokine CCL5 ; chemokine CXCL10 ; enzyme activity ; innate immunity ; interferon-beta ; pathogenesis ; polyproteins ; proteinases ; covid19
Language	English
Dates of publication	2014-02
Size	p. 64-70.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2013.11.040
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases.

Báez-Santos, Yahira M / Barraza, Scott J / Wilson, Michael W / Agius, Michael P / Mielech, Anna M / Davis, Nicole M / Baker, Susan C / Larsen, Scott D / Mesecar, Andrew D

Journal of medicinal chemistry

2014 Volume 57, Issue 6, Page(s) 2393–2412

Abstract: Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected ... ...

Abstract	Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.
MeSH term(s)	Animals ; Antiviral Agents/chemical synthesis ; Antiviral Agents/metabolism ; Antiviral Agents/pharmacology ; Cell Survival/drug effects ; Chlorocebus aethiops ; Coronavirus/drug effects ; Coronavirus/enzymology ; Cysteine Proteinase Inhibitors/chemical synthesis ; Cysteine Proteinase Inhibitors/pharmacology ; Humans ; Indicators and Reagents ; Molecular Conformation ; Mutagenesis/drug effects ; Papain/chemistry ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/metabolism ; Phospholipase A2 Inhibitors/chemical synthesis ; Phospholipase A2 Inhibitors/pharmacology ; Protein Binding ; Severe acute respiratory syndrome-related coronavirus/drug effects ; Severe acute respiratory syndrome-related coronavirus/enzymology ; Structure-Activity Relationship ; Vero Cells ; X-Ray Diffraction
Chemical Substances	Antiviral Agents ; Cysteine Proteinase Inhibitors ; Indicators and Reagents ; Phospholipase A2 Inhibitors ; Peptide Hydrolases (EC 3.4.-) ; Papain (EC 3.4.22.2)
Keywords	covid19
Language	English
Publishing date	2014-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm401712t
Database	MEDical Literature Analysis and Retrieval System OnLINE

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