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Article ; Online: Editorial overview: Special issue on antiviral strategies in Current Opinion in Virology.

Plemper, Richard K

2021 Volume 50, Page(s) 95–96

MeSH term(s)	Antiviral Agents/therapeutic use ; Humans ; Virology
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2021-08-20
Publishing country	Netherlands
Document type	Editorial ; Introductory Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2021.07.008
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Article ; Online: Measles Resurgence and Drug Development.

Plemper, Richard K

Current opinion in virology

2020 Volume 41, Page(s) 8–17

Abstract: Measles caused an estimated minimum of one million fatalities annually before vaccination. Outstanding progress towards controlling the virus has been made since the measles vaccine was introduced, but reduction of measles case-fatalities has stalled at ... ...

Abstract	Measles caused an estimated minimum of one million fatalities annually before vaccination. Outstanding progress towards controlling the virus has been made since the measles vaccine was introduced, but reduction of measles case-fatalities has stalled at around 100,000 annually for the last decade and a 2019 resurgence in several geographical regions threatens some of these past accomplishments. Whereas measles eradication through vaccination is feasible, a potentially open-ended endgame of elimination may loom. Other than doubling-down on existing approaches, is it worthwhile to augment vaccination efforts with antiviral therapeutics to solve the conundrum? This question is hypothetical at present, since no drugs have yet been approved specifically for the treatment of measles, or infection by any other pathogen of the paramyxovirus family. This article will consider obstacles that have hampered anti-measles and anti-paramyxovirus drug development, discuss MeV-specific challenges of clinical testing, and define drug properties suitable to address some of these problems.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Drug Development ; Global Health ; Humans ; Measles/epidemiology ; Measles/prevention & control ; Measles/virology ; Measles Vaccine/administration & dosage ; Measles virus/drug effects ; Measles virus/genetics ; Measles virus/immunology
Chemical Substances	Antiviral Agents ; Measles Vaccine
Language	English
Publishing date	2020-04-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2020.02.007
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Article ; Online: 4'-Fluorouridine Is a Broad-Spectrum Orally Available First-Line Antiviral That May Improve Pandemic Preparedness.

Lieber, Carolin M / Plemper, Richard K

DNA and cell biology

2022 Volume 41, Issue 8, Page(s) 699–704

Abstract: The COVID-19 pandemic has highlighted the urgent need for the development of broad-spectrum antivirals to enhance preparedness against future spillover of zoonotic viruses with pandemic potential into the human population. Currently, the direct-acting ... ...

Abstract	The COVID-19 pandemic has highlighted the urgent need for the development of broad-spectrum antivirals to enhance preparedness against future spillover of zoonotic viruses with pandemic potential into the human population. Currently, the direct-acting orally available SARS-CoV-2 inhibitors molnupiravir and paxlovid are approved for human use under emergency use authorization. A promising next-generation therapeutic candidate is the orally available ribonucleoside analog 4'-fluorouridine (4'-FlU) that had potent antiviral efficacy against different viral targets, including SARS-CoV-2 in human organoids and animal models. Although a nucleoside analog inhibitor such as molnupiravir that targets the viral RNA-dependent RNA polymerase (RdRP) complex, 4'-FlU showed a distinct mechanism of activity, delayed chain termination, compared with molnupiravir's induction of viral error catastrophe. This review will focus on some currently approved and emerging medicines developed against SARS-CoV-2, examining their potential to form a pharmacological first-line defense against zoonotic viruses with pandemic potential.
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Humans ; Pandemics ; SARS-CoV-2 ; Uracil Nucleotides ; COVID-19 Drug Treatment
Chemical Substances	4'-fluorouridine ; Antiviral Agents ; Uracil Nucleotides
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1024454-2
ISSN	1557-7430 ; 0198-0238 ; 1044-5498
ISSN (online)	1557-7430
ISSN	0198-0238 ; 1044-5498
DOI	10.1089/dna.2022.0312
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Article ; Online: The impact of high-resolution structural data on stemming the COVID-19 pandemic.

Cox, Robert M / Plemper, Richard K

Current opinion in virology

2021 Volume 49, Page(s) 127–138

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has had a catastrophic impact on human health and the world economy. The response of the scientific community was unparalleled, and a combined global effort has resulted in the creation of vaccines in a ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic has had a catastrophic impact on human health and the world economy. The response of the scientific community was unparalleled, and a combined global effort has resulted in the creation of vaccines in a shorter time frame than previously unimaginable. Reflecting this concerted effort, the structural analysis of the etiological agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has progressed with an unprecedented pace. Since the onset of the pandemic, over 1000 high-resolution structures of a broad range of SARS-CoV-2 proteins have been solved and made publicly available. These structures have aided in the identification of numerous potential druggable targets and have contributed to the design of different vaccine candidates. This opinion article will discuss the impact of high-resolution structures in understanding SARS-CoV-2 biology and explore their role in the development of vaccines and antivirals.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/epidemiology ; COVID-19/prevention & control ; COVID-19 Vaccines/immunology ; COVID-19 Vaccines/therapeutic use ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/chemistry ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/chemistry ; Humans ; SARS-CoV-2/chemistry ; SARS-CoV-2/drug effects ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/antagonists & inhibitors ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/immunology ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; COVID-19 Vaccines ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Coronavirus 3C Proteases (EC 3.4.22.28)
Language	English
Publishing date	2021-06-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2021.05.005
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Article ; Online: Next-generation direct-acting influenza therapeutics.

Toots, Mart / Plemper, Richard K

Translational research : the journal of laboratory and clinical medicine

2020 Volume 220, Page(s) 33–42

Abstract: Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent ... ...

Abstract	Influenza viruses are a major threat to human health globally. In addition to further improving vaccine prophylaxis, disease management through antiviral therapeutics constitutes an important component of the current intervention strategy to prevent advance to complicated disease and reduce case-fatality rates. Standard-of-care is treatment with neuraminidase inhibitors that prevent viral dissemination. In 2018, the first mechanistically new influenza drug class for the treatment of uncomplicated seasonal influenza in 2 decades was approved for human use. Targeting the PA endonuclease subunit of the viral polymerase complex, this class suppresses viral replication. However, the genetic barrier against viral resistance to both drug classes is low, pre-existing resistance is observed in circulating strains, and resistant viruses are pathogenic and transmit efficiently. Addressing the resistance problem has emerged as an important objective for the development of next-generation influenza virus therapeutics. This review will discuss the status of influenza therapeutics including the endonuclease inhibitor baloxavir marboxil after its first year of clinical use and evaluate a subset of direct-acting antiviral candidates in different stages of preclinical and clinical development.
MeSH term(s)	Amides/therapeutic use ; Antibodies, Neutralizing/blood ; Antiviral Agents/therapeutic use ; Cytidine/analogs & derivatives ; Dibenzothiepins ; Drug Resistance, Viral ; Humans ; Hydroxylamines ; Influenza, Human/drug therapy ; Morpholines ; Neuraminidase/antagonists & inhibitors ; Oxazines/therapeutic use ; Pyrazines/therapeutic use ; Pyridines/therapeutic use ; Pyridones ; RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Ribonucleosides/therapeutic use ; Thiepins/therapeutic use ; Triazines/therapeutic use ; Virus Replication/drug effects
Chemical Substances	Amides ; Antibodies, Neutralizing ; Antiviral Agents ; Dibenzothiepins ; Hydroxylamines ; Morpholines ; Oxazines ; Pyrazines ; Pyridines ; Pyridones ; Ribonucleosides ; Thiepins ; Triazines ; baloxavir (4G86Y4JT3F) ; Cytidine (5CSZ8459RP) ; RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; Neuraminidase (EC 3.2.1.18) ; favipiravir (EW5GL2X7E0) ; molnupiravir (YA84KI1VEW)
Keywords	covid19
Language	English
Publishing date	2020-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2246684-8
ISSN	1878-1810 ; 1532-6543 ; 1931-5244
ISSN (online)	1878-1810 ; 1532-6543
ISSN	1931-5244
DOI	10.1016/j.trsl.2020.01.005
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Article ; Online: Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition.

Aggarwal, Megha / Plemper, Richard K

Viruses

2020 Volume 12, Issue 3

Abstract: Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV) ...

Abstract	Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre- and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Binding Sites ; Drug Discovery/methods ; Humans ; Models, Molecular ; Paramyxoviridae Infections/drug therapy ; Paramyxoviridae Infections/virology ; Paramyxovirinae/drug effects ; Paramyxovirinae/physiology ; Pneumovirus/drug effects ; Pneumovirus/physiology ; Pneumovirus Infections/drug therapy ; Pneumovirus Infections/virology ; Protein Binding ; Structure-Activity Relationship ; Virus Internalization/drug effects
Chemical Substances	Antiviral Agents
Keywords	covid19
Language	English
Publishing date	2020-03-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v12030342
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Article ; Online: Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection.

Ngo, Vu L / Lieber, Carolin M / Kang, Hae-Ji / Sakamoto, Kaori / Kuczma, Michal / Plemper, Richard K / Gewirtz, Andrew T

Cell host & microbe

2024 Volume 32, Issue 3, Page(s) 335–348.e8

Abstract: Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented ... ...

Abstract	Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AMs). In SFB-negative mice, AMs were quickly depleted as RVI progressed. In contrast, AMs from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AMs from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AMs into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.
MeSH term(s)	Animals ; Mice ; Macrophages, Alveolar ; Gastrointestinal Microbiome ; Phagocytosis ; Interferons ; Bacteria ; Virus Diseases
Chemical Substances	Interferons (9008-11-1)
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2024.01.002
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Article: Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection.

Ngo, Vu L / Lieber, Carolin M / Kang, Hae-Ji / Sakamoto, Kaori / Kuczma, Michal / Plemper, Richard K / Gewirtz, Andrew T

bioRxiv : the preprint server for biology

2024

Abstract	Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM). In SFB-negative mice, AM were quickly depleted as RVI progressed. In contrast, AM from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity. One sentence summary: Intestinal segmented filamentous bacteria reprogram alveolar macrophages promoting nonphlogistic defense against respiratory viruses.
Language	English
Publishing date	2024-01-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.21.558814
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Article ; Online: Editorial overview: Antiviral strategies: Antiviral drug development for single-stranded RNA viruses.

Brinton, Margo A / Plemper, Richard K

Current opinion in virology

2019 Volume 35, Page(s) iii–v

MeSH term(s)	Antiviral Agents/pharmacology ; Coronavirus/drug effects ; Drug Development/methods ; Flaviviridae/drug effects ; Hepacivirus/drug effects ; Humans ; Influenza, Human/drug therapy ; Influenza, Human/immunology ; RNA Viruses/drug effects ; Rabies/drug therapy ; Sex Factors
Chemical Substances	Antiviral Agents
Keywords	covid19
Language	English
Publishing date	2019-05-29
Publishing country	Netherlands
Document type	Editorial ; Introductory Journal Article
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2019.05.011
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Article ; Online: Progress and pitfalls of a year of drug repurposing screens against COVID-19.

Sourimant, Julien / Aggarwal, Megha / Plemper, Richard K

Current opinion in virology

2021 Volume 49, Page(s) 183–193

Abstract: Near the end of 2019, a new betacoronavirus started to efficiently transmit between humans, resulting in the current COVID-19 pandemic. Unprecedented worldwide efforts were made to identify and repurpose antiviral therapeutics from collections of ... ...

Abstract	Near the end of 2019, a new betacoronavirus started to efficiently transmit between humans, resulting in the current COVID-19 pandemic. Unprecedented worldwide efforts were made to identify and repurpose antiviral therapeutics from collections of approved drugs and known bioactive compounds. Typical pitfalls of this approach (promiscuous/cytotoxic compounds leading to false positives), combined with bypassing antiviral drug development parameters due to urgency have resulted in often disappointing outcomes. A flood of publications, press-releases, and media posts, created confusion in the general public and sometime mobilized precious resources for clinical trials with minimal prospect of success. Breakthroughs have been made, not in the laboratory but in the clinic, resulting from the empiric identification of mitigators of clinical signs such as the discovery of improved disease management through immunomodulators. This opinion piece will aim to capture some of the lessons that we believe the COVID-19 pandemic has taught about drug repurposing screens.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; COVID-19/epidemiology ; Disease Management ; Drug Evaluation, Preclinical ; Drug Repositioning ; Humans ; SARS-CoV-2/drug effects ; Small Molecule Libraries
Chemical Substances	Antiviral Agents ; Small Molecule Libraries
Language	English
Publishing date	2021-06-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2611378-8
ISSN	1879-6265 ; 1879-6257
ISSN (online)	1879-6265
ISSN	1879-6257
DOI	10.1016/j.coviro.2021.06.004
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