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Article ; Online: How ISG15 combats viral infection.

Freitas, Brendan T / Scholte, Florine E M / Bergeron, Éric / Pegan, Scott D

2020 Volume 286, Page(s) 198036

Abstract: Interferon (IFN)-stimulated gene product 15 (ISG15) is a ubiquitin-like protein critical for the control of microbial infections. ISG15 appears to serve a wide variety of functions, which regulate multiple cellular responses contributing to the ... ...

Abstract	Interferon (IFN)-stimulated gene product 15 (ISG15) is a ubiquitin-like protein critical for the control of microbial infections. ISG15 appears to serve a wide variety of functions, which regulate multiple cellular responses contributing to the development of an antiviral state. ISG15 is a versatile molecule directly modulating both host and virus protein function which regulate many signaling pathways, including its own synthesis. Here we review the various roles ISG15 plays in the antiviral immune response, and examine the mechanisms by which viruses attempt to mitigate or exploit ISG15 activity.
MeSH term(s)	Animals ; Cytokines/genetics ; Cytokines/metabolism ; Humans ; Immunity, Innate/immunology ; Interferon Type I/immunology ; Macrophages/immunology ; Mice ; Neutrophils/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology ; Ubiquitins/genetics ; Ubiquitins/metabolism ; Viral Proteins/metabolism ; Virus Diseases/immunology ; Virus Internalization ; Virus Replication/immunology
Chemical Substances	Cytokines ; Interferon Type I ; Ubiquitins ; Viral Proteins ; ISG15 protein, human (60267-61-0)
Keywords	covid19
Language	English
Publishing date	2020-05-31
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.198036
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Article: How ISG15 combats viral infection

Freitas, Brendan T / Scholte, Florine E.M / Bergeron, Éric / Pegan, Scott D

Elsevier B.V. Virus research. 2020 Sept., v. 286

2020

Abstract	Interferon (IFN)-stimulated gene product 15 (ISG15) is a ubiquitin-like protein critical for the control of microbial infections. ISG15 appears to serve a wide variety of functions, which regulate multiple cellular responses contributing to the development of an antiviral state. ISG15 is a versatile molecule directly modulating both host and virus protein function which regulate many signaling pathways, including its own synthesis. Here we review the various roles ISG15 plays in the antiviral immune response, and examine the mechanisms by which viruses attempt to mitigate or exploit ISG15 activity.
Keywords	genes ; immune response ; interferons ; signal transduction ; viral proteins ; viruses
Language	English
Dates of publication	2020-09
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	605780-9
ISSN	1872-7492 ; 0168-1702
ISSN (online)	1872-7492
ISSN	0168-1702
DOI	10.1016/j.virusres.2020.198036
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Flipping the substrate preference of Hazara virus ovarian tumour domain protease through structure-based mutagenesis.

Dzimianski, John V / Mace, Savannah L / Williams, Isabelle L / Freitas, Brendan T / Pegan, Scott D

Acta crystallographica. Section D, Structural biology

2020 Volume 76, Issue Pt 11, Page(s) 1114–1123

Abstract: Nairoviruses are arthropod-borne viruses with a nearly global geographical distribution. Several are known causative agents of human disease, including Crimean-Congo hemorrhagic fever virus (CCHFV), which has a case fatality rate that can exceed 30%. ... ...

Abstract	Nairoviruses are arthropod-borne viruses with a nearly global geographical distribution. Several are known causative agents of human disease, including Crimean-Congo hemorrhagic fever virus (CCHFV), which has a case fatality rate that can exceed 30%. Nairoviruses encode an ovarian tumour domain protease (OTU) that can suppress the innate immune response by reversing post-translational modifications by ubiquitin (Ub) and/or interferon-stimulated gene product 15 (ISG15). As a result, the OTU has been identified as a potential target for the development of CCHFV therapeutics. Despite sharing the same general fold, nairoviral OTUs show structural and enzymatic diversity. The CCHFV OTU, for example, possesses activity towards both Ub and ISG15, while the Hazara virus (HAZV) OTU interacts exclusively with Ub. Virology studies focused on the OTU have mostly been restricted to CCHFV, which requires BSL-4 containment facilities. Although HAZV has been proposed as a BSL-2 alternative, differences in the engagement of substrates by CCHFV and HAZV OTUs may present complicating factors when trying to model one using the other. To understand the molecular underpinnings of the differences in activity, a 2.78 Å resolution crystal structure of HAZV OTU bound to Ub was solved. Using structure-guided site-directed mutagenesis, HAZV OTUs were engineered with altered or eliminated deubiquitinase activity, including one with an exclusive activity for ISG15. Additionally, analysis of the structure yielded insights into the difference in inhibition observed between CCHFV and HAZV OTUs with a Ub-based inhibitor. These new insights present opportunities to utilize HAZV as a model system to better understand the role of the OTU in the context of infection.
MeSH term(s)	Models, Molecular ; Nairovirus/enzymology ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/metabolism ; Protein Binding ; Protein Domains ; Ubiquitin/chemistry ; Ubiquitin/metabolism ; Viral Proteins/chemistry ; Viral Proteins/metabolism
Chemical Substances	Ubiquitin ; Viral Proteins ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2020-10-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2968623-4
ISSN	2059-7983 ; 0907-4449
ISSN (online)	2059-7983
ISSN	0907-4449
DOI	10.1107/S2059798320012875
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Article: How ISG15 combats viral infection

Freitas, Brendan T / Scholte, Florine E M / Bergeron, Éric / Pegan, Scott D

Virus Res

Abstract	Interferon (IFN)-stimulated gene product 15 (ISG15) is a ubiquitin-like protein critical for the control of microbial infections. ISG15 appears to serve a wide variety of functions, which regulate multiple cellular responses contributing to the development of an antiviral state. ISG15 is a versatile molecule directly modulating both host and virus protein function which regulate many signaling pathways, including its own synthesis. Here we review the various roles ISG15 plays in the antiviral immune response, and examine the mechanisms by which viruses attempt to mitigate or exploit ISG15 activity.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #625038
Database	COVID19

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Article ; Online: The Structure and Immune Regulatory Implications of the Ubiquitin-Like Tandem Domain Within an Avian 2'-5' Oligoadenylate Synthetase-Like Protein.

Shepard, Justin D / Freitas, Brendan T / Rodriguez, Sergio E / Scholte, Florine E M / Baker, Kailee / Hutchison, Madelyn R / Longo, Jaron E / Miller, Holden C / O'Boyle, Brady M / Tandon, Aarushi / Zhao, Peng / Grimsey, Neil J / Wells, Lance / Bergeron, Éric / Pegan, Scott D

Frontiers in immunology

2022 Volume 12, Page(s) 794664

Abstract: Post-translational modification of host and viral proteins by ubiquitin and ubiquitin-like proteins plays a key role in a host's ability to mount an effective immune response. Avian species lack a ubiquitin-like protein found in mammals and other non- ... ...

Abstract	Post-translational modification of host and viral proteins by ubiquitin and ubiquitin-like proteins plays a key role in a host's ability to mount an effective immune response. Avian species lack a ubiquitin-like protein found in mammals and other non-avian reptiles; interferon stimulated gene product 15 (ISG15). ISG15 serves as a messenger molecule and can be conjugated to both host and viral proteins leading them to be stabilized, degraded, or sequestered. Structurally, ISG15 is comprised of a tandem ubiquitin-like domain (Ubl), which serves as the motif for post-translational modification. The 2'-5' oligoadenylate synthetase-like proteins (OASL) also encode two Ubl domains in series near its C-terminus which binds OASL to retinoic acid inducible gene-I (RIG-I). This protein-protein interaction increases the sensitivity of RIG-I and results in an enhanced production of type 1 interferons and a robust immune response. Unlike human and other mammalian OASL homologues, avian OASLs terminate their tandem Ubl domains with the same LRLRGG motif found in ubiquitin and ISG15, a motif required for their conjugation to proteins. Chickens, however, lack RIG-I, raising the question of structural and functional characteristics of chicken OASL (chOASL). By investigating chOASL, the evolutionary history of viruses with deubiquitinases can be explored and drivers of species specificity for these viruses may be uncovered. Here we show that the chOASL tandem Ubl domains shares structural characteristics with mammalian ISG15, and that chOASL can oligomerize and conjugate to itself. In addition, the ISG15-like features of avian OASLs and how they impact interactions with viral deubiquitinases and deISGylases are explored.
MeSH term(s)	2',5'-Oligoadenylate Synthetase/chemistry ; 2',5'-Oligoadenylate Synthetase/metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; Chickens ; Humans ; Immunomodulation ; Mass Spectrometry ; Models, Biological ; Protein Binding ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Processing, Post-Translational ; Proteolysis ; Structure-Activity Relationship ; Ubiquitin/chemistry ; Ubiquitin/metabolism ; Viral Proteins/chemistry ; Viral Proteins/metabolism
Chemical Substances	Ubiquitin ; Viral Proteins ; 2',5'-Oligoadenylate Synthetase (EC 2.7.7.84)
Language	English
Publishing date	2022-01-04
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.794664
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Article ; Online: The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease.

Reynolds, Nathanael D / Aceves, Nathalie M / Liu, Jinny L / Compton, Jaimee R / Leary, Dagmar H / Freitas, Brendan T / Pegan, Scott D / Doctor, Katarina Z / Wu, Fred Y / Hu, Xin / Legler, Patricia M

ACS infectious diseases

2021 Volume 7, Issue 6, Page(s) 1483–1502

Abstract: Viral proteases are highly specific and recognize conserved cleavage site sequences of ∼6-8 amino acids. Short stretches of homologous host-pathogen sequences (SSHHPS) can be found spanning the viral protease cleavage sites. We hypothesized that these ... ...

Abstract	Viral proteases are highly specific and recognize conserved cleavage site sequences of ∼6-8 amino acids. Short stretches of homologous host-pathogen sequences (SSHHPS) can be found spanning the viral protease cleavage sites. We hypothesized that these sequences corresponded to specific host protein targets since >40 host proteins have been shown to be cleaved by Group IV viral proteases and one Group VI viral protease. Using PHI-BLAST and the viral protease cleavage site sequences, we searched the human proteome for host targets and analyzed the hit results. Although the polyprotein and host proteins related to the suppression of the innate immune responses may be the primary targets of these viral proteases, we identified other cleavable host proteins. These proteins appear to be related to the virus-induced phenotype associated with Group IV viruses, suggesting that information about viral pathogenesis may be extractable directly from the viral genome sequence. Here we identify sequences cleaved by the SARS-CoV-2 papain-like protease (PLpro)
MeSH term(s)	Amino Acid Sequence ; Cardiac Myosins/chemistry ; Forkhead Transcription Factors/chemistry ; Humans ; Myosin Heavy Chains/chemistry ; Papain/metabolism ; Peptide Hydrolases/metabolism ; Protein S/chemistry ; Receptor, ErbB-4/chemistry ; SARS-CoV-2/enzymology ; Viral Proteases/metabolism
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors ; MYH6 protein, human ; MYH7 protein, human ; PROS1 protein, human ; Protein S ; ERBB4 protein, human (EC 2.7.10.1) ; Receptor, ErbB-4 (EC 2.7.10.1) ; Peptide Hydrolases (EC 3.4.-) ; Viral Proteases (EC 3.4.-) ; Papain (EC 3.4.22.2) ; Cardiac Myosins (EC 3.6.1.-) ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2021-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.0c00866
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Article ; Online: Determining the molecular drivers of species-specific interferon-stimulated gene product 15 interactions with nairovirus ovarian tumor domain proteases.

Dzimianski, John V / Scholte, Florine E M / Williams, Isabelle L / Langley, Caroline / Freitas, Brendan T / Spengler, Jessica R / Bergeron, Éric / Pegan, Scott D

PloS one

2019 Volume 14, Issue 12, Page(s) e0226415

Abstract: Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 ...

Abstract	Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection.
MeSH term(s)	Amino Acid Sequence ; Animals ; Antigens, Neoplasm/chemistry ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Crystallography, X-Ray ; Cytokines/metabolism ; HEK293 Cells ; Host Specificity/genetics ; Host-Pathogen Interactions/genetics ; Humans ; Mice ; Models, Molecular ; Nairovirus/classification ; Nairovirus/enzymology ; Nairovirus/genetics ; Peptide Hydrolases/chemistry ; Peptide Hydrolases/genetics ; Peptide Hydrolases/metabolism ; Phylogeny ; Protein Binding/genetics ; Protein Interaction Domains and Motifs/genetics ; Sequence Homology ; Sheep ; Species Specificity ; Ubiquitin/metabolism ; Ubiquitins/metabolism ; Viral Proteins/chemistry ; Viral Proteins/genetics
Chemical Substances	Antigens, Neoplasm ; Cytokines ; Ubiquitin ; Ubiquitins ; Viral Proteins ; ovarian tumor associated antigen ; ISG15 protein, human (60267-61-0) ; Peptide Hydrolases (EC 3.4.-)
Keywords	covid19
Language	English
Publishing date	2019-12-23
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	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0226415
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Article ; Online: Single-dose replicon particle vaccine provides complete protection against Crimean-Congo hemorrhagic fever virus in mice.

Scholte, Florine E M / Spengler, Jessica R / Welch, Stephen R / Harmon, Jessica R / Coleman-McCray, JoAnn D / Freitas, Brendan T / Kainulainen, Markus H / Pegan, Scott D / Nichol, Stuart T / Bergeron, Éric / Spiropoulou, Christina F

Emerging microbes & infections

2019 Volume 8, Issue 1, Page(s) 575–578

MeSH term(s)	Animals ; Female ; Hemorrhagic Fever Virus, Crimean-Congo/genetics ; Hemorrhagic Fever Virus, Crimean-Congo/immunology ; Hemorrhagic Fever, Crimean/immunology ; Hemorrhagic Fever, Crimean/prevention & control ; Hemorrhagic Fever, Crimean/virology ; Humans ; Mice ; Mice, Knockout ; Replicon ; Spain ; Vaccination ; Viral Proteins/genetics ; Viral Proteins/immunology ; Viral Vaccines/administration & dosage ; Viral Vaccines/genetics ; Viral Vaccines/immunology ; Virion/genetics ; Virion/immunology
Chemical Substances	Viral Proteins ; Viral Vaccines
Language	English
Publishing date	2019-07-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2681359-2
ISSN	2222-1751 ; 2222-1751
ISSN (online)	2222-1751
ISSN	2222-1751
DOI	10.1080/22221751.2019.1601030
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Article ; Online: Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses.

Freitas, Brendan T / Ahiadorme, Daniil A / Bagul, Rahul S / Durie, Ian A / Ghosh, Samir / Hill, Jarvis / Kramer, Naomi E / Murray, Jackelyn / O'Boyle, Brady M / Onobun, Emmanuel / Pirrone, Michael G / Shepard, Justin D / Enos, Suzanne / Subedi, Yagya P / Upadhyaya, Kapil / Tripp, Ralph A / Cummings, Brian S / Crich, David / Pegan, Scott D

ACS infectious diseases

2022 Volume 8, Issue 3, Page(s) 596–611

Abstract: Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a ... ...

Abstract	Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for K48 polyubiquitin and ISG15 originating from certain species. The PLpro of BtSCoV-Rf1.2004 was used as a tool alongside PLpro of CoV-1 and CoV-2 to design 30 novel noncovalent drug-like pan subgroup 2b PLpro inhibitors that included determining the effects of using previously unexplored core linkers within these compounds. Two crystal structures of BtSCoV-Rf1.2004 PLpro bound to these inhibitors aided in compound design as well as shared structural features among subgroup 2b proteases. Screening of these three subgroup 2b PLpros against this novel set of inhibitors along with cytotoxicity studies provide new directions for pan-coronavirus subgroup 2b antiviral development of PLpro inhibitors.
MeSH term(s)	Animals ; COVID-19 ; Protease Inhibitors ; Severe acute respiratory syndrome-related coronavirus ; SARS-CoV-2 ; Ubiquitin/metabolism
Chemical Substances	Protease Inhibitors ; Ubiquitin
Language	English
Publishing date	2022-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.1c00631
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Article ; Online: Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease.

Freitas, Brendan T / Durie, Ian A / Murray, Jackelyn / Longo, Jaron E / Miller, Holden C / Crich, David / Hogan, Robert Jeff / Tripp, Ralph A / Pegan, Scott D

ACS infectious diseases

2020 Volume 6, Issue 8, Page(s) 2099–2109

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, is a novel human betacoronavirus that is rapidly spreading worldwide. The outbreak currently includes over 3.7 million cases and 260,000 fatalities. As a ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, is a novel human betacoronavirus that is rapidly spreading worldwide. The outbreak currently includes over 3.7 million cases and 260,000 fatalities. As a betacoronavirus, SARS-CoV-2 encodes for a papain-like protease (PLpro) that is likely responsible for cleavage of the coronavirus (CoV) viral polypeptide. The PLpro is also responsible for suppression of host innate immune responses by virtue of its ability to reverse host ubiquitination and ISGylation events. Here, the biochemical activity of SARS-CoV-2 PLpro against ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15) substrates is evaluated, revealing that the protease has a marked reduction in its ability to process K48 linked Ub substrates compared to its counterpart in SARS-CoV. Additionally, its substrate activity more closely mirrors that of the PLpro from the Middle East respiratory syndrome coronavirus and prefers ISG15s from certain species including humans. Additionally, naphthalene based PLpro inhibitors are shown to be effective at halting SARS-CoV-2 PLpro activity as well as SARS-CoV-2 replication.
MeSH term(s)	Amino Acid Sequence ; Animals ; Betacoronavirus/enzymology ; Binding Sites ; COVID-19 ; Chlorocebus aethiops ; Coronavirus 3C Proteases ; Coronavirus Infections/virology ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Cytokines/antagonists & inhibitors ; Cytokines/chemistry ; Cytokines/metabolism ; Deubiquitinating Enzymes/antagonists & inhibitors ; Humans ; Naphthalenes/pharmacology ; Pandemics ; Pneumonia, Viral/virology ; Protein Binding ; Protein Conformation ; SARS-CoV-2 ; Substrate Specificity ; Ubiquitin/metabolism ; Ubiquitins/antagonists & inhibitors ; Ubiquitins/chemistry ; Ubiquitins/metabolism ; Vero Cells ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/metabolism ; Virus Replication/drug effects
Chemical Substances	Cytokines ; Naphthalenes ; Ubiquitin ; Ubiquitins ; Viral Nonstructural Proteins ; naphthalene (2166IN72UN) ; ISG15 protein, human (60267-61-0) ; Deubiquitinating Enzymes (EC 3.4.19.12) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Keywords	covid19
Language	English
Publishing date	2020-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.0c00168
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