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  1. Article: CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication

    Logue, James / Melville, Victoria M / Ardanuy, Jeremy / Frieman, Matthew B

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world's healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus ... ...

    Abstract The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world's healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus replication cycle have been developed however, effective late-stage therapeutical targets have yet to be identified. To that end, our lab identified that 2',3' cyclic-nucleotide 3'-phosphodiesterase (CNP) inhibits SARS-CoV-2 virion assembly. We show that CNP inhibits the generation of new SARS-CoV-2 virions, reducing intracellular titers without inhibiting viral structural protein translation. Additionally, we show that targeting of CNP to mitochondria is necessary for inhibition, blocking mitochondrial depolarization and implicating CNP's proposed role as an inhibitor of the mitochondrial permeabilization transition pore (mPTP) as the mechanism of virion assembly inhibition. We also demonstrate that an adenovirus expressing virus expressing both human ACE2 and CNP inhibits SARS-CoV-2 titers to undetectable levels in lungs of mice. Collectively, this work shows the potential of CNP to be a new SARS-CoV-2 antiviral target.
    Language English
    Publishing date 2023-12-19
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.06.09.544327
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication in vitro and in vivo.

    Logue, James / Melville, Victoria M / Ardanuy, Jeremy / Frieman, Matthew B

    PLoS pathogens

    2023  Volume 19, Issue 12, Page(s) e1011870

    Abstract: The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world's healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus ... ...

    Abstract The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world's healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus replication cycle have been developed however, effective late-stage therapeutical targets have yet to be identified. To that end, our lab identified that 2',3' cyclic-nucleotide 3'-phosphodiesterase (CNP) inhibits SARS-CoV-2 virion assembly. We show that CNP inhibits the generation of new SARS-CoV-2 virions, reducing intracellular titers without inhibiting viral structural protein translation. Additionally, we show that targeting of CNP to mitochondria is necessary for inhibition, blocking mitochondrial depolarization and implicating CNP's proposed role as an inhibitor of the mitochondrial permeabilization transition pore (mPTP) as the mechanism of virion assembly inhibition. We also demonstrate that an adenovirus expressing virus expressing both human ACE2 and CNP inhibits SARS-CoV-2 titers to undetectable levels in lungs of mice. Collectively, this work shows the potential of CNP to be a new SARS-CoV-2 antiviral target.
    MeSH term(s) Mice ; Humans ; Animals ; SARS-CoV-2 ; COVID-19/metabolism ; Pandemics ; Mitochondria/metabolism ; Virus Assembly ; Antiviral Agents/metabolism
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2023-12-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1011870
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: COVID-19: Knowns, Unknowns, and Questions.

    Weston, Stuart / Frieman, Matthew B

    mSphere

    2020  Volume 5, Issue 2

    Abstract: The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the Hubei province in China in late 2019 demonstrates the epidemic potential of coronaviruses. The rapid spread of this virus across the world in only 2 months ... ...

    Abstract The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the Hubei province in China in late 2019 demonstrates the epidemic potential of coronaviruses. The rapid spread of this virus across the world in only 2 months highlights the transmissibility of this family of viruses and the significant morbidity and mortality that they can cause. We highlight the current state of knowledge of coronavirus biology while answering questions concerning the current outbreak of SARS-CoV-2.
    MeSH term(s) Betacoronavirus ; COVID-19 ; China/epidemiology ; Coronavirus Infections/epidemiology ; Coronavirus Infections/transmission ; Humans ; Pandemics ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/transmission ; Risk Factors ; SARS-CoV-2
    Keywords covid19
    Language English
    Publishing date 2020-03-18
    Publishing country United States
    Document type Journal Article
    ISSN 2379-5042
    ISSN (online) 2379-5042
    DOI 10.1128/mSphere.00203-20
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Using Yeast to Identify Coronavirus-Host Protein Interactions.

    Weston, Stuart / Frieman, Matthew

    Methods in molecular biology (Clifton, N.J.)

    2020  Volume 2203, Page(s) 205–221

    Abstract: We have developed a screening system using the yeast Saccharomyces cerevisiae to identify eukaryotic genes involved in the replication of mammalian viruses. Yeast come with various advantages, but in the context of coronavirus research and the system ... ...

    Abstract We have developed a screening system using the yeast Saccharomyces cerevisiae to identify eukaryotic genes involved in the replication of mammalian viruses. Yeast come with various advantages, but in the context of coronavirus research and the system outlined here, they are simple and easy to work with and can be used at biosafety level 2. The system involves inducible expression of individual viral proteins and identification of detrimental phenotypes in the yeast. Yeast knockout and overexpression libraries can then be used for genome-wide screening of host proteins that provide a suppressor phenotype. From the yeast hits, a narrowed list of candidate genes can be produced to investigate for roles in viral replication. Since the system only requires expression of viral proteins, it can be used for any current or emerging virus, regardless of biocontainment requirements and ability to culture the virus. In this chapter, we will outline the protocols that can be used to take advantage of S. cerevisiae as a tool to advance understanding of how viruses interact with eukaryotic cells.
    MeSH term(s) Coronavirus/pathogenicity ; Coronavirus/physiology ; Host-Pathogen Interactions/physiology ; Plasmids ; Saccharomyces cerevisiae/genetics ; Viral Proteins/genetics ; Viral Proteins/isolation & purification ; Virus Replication
    Chemical Substances Viral Proteins
    Keywords covid19
    Language English
    Publishing date 2020-07-29
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-0900-2_15
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: The continued epidemic threat of SARS-CoV-2 and implications for the future of global public health.

    Sheahan, Timothy P / Frieman, Matthew B

    Current opinion in virology

    2020  Volume 40, Page(s) 37–40

    Abstract: A new coronavirus (CoV) called SARS-CoV-2 emerged in Wuhan, China in December 2019 as the etiological agent of a viral pneumonia called COVID-19. The global spread of SARS-CoV-2 has been so extensive that the WHO declared COVID-19 a pandemic on March 11, ...

    Abstract A new coronavirus (CoV) called SARS-CoV-2 emerged in Wuhan, China in December 2019 as the etiological agent of a viral pneumonia called COVID-19. The global spread of SARS-CoV-2 has been so extensive that the WHO declared COVID-19 a pandemic on March 11, 2020. Below, we discuss the emergence of SARS-CoV-2 and provide the historical context, which strongly suggests emerging CoVs provide an immediate threat to global public health and will continue to do so in the future.
    MeSH term(s) Animals ; Betacoronavirus ; COVID-19 ; China/epidemiology ; Communicable Diseases, Emerging/epidemiology ; Communicable Diseases, Emerging/virology ; Coronavirus Infections/epidemiology ; Disease Reservoirs/virology ; Global Health ; Humans ; Pandemics ; Pneumonia, Viral/epidemiology ; SARS-CoV-2 ; World Health Organization
    Keywords covid19
    Language English
    Publishing date 2020-06-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2611378-8
    ISSN 1879-6265 ; 1879-6257
    ISSN (online) 1879-6265
    ISSN 1879-6257
    DOI 10.1016/j.coviro.2020.05.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The art of war: battles between virus and host.

    Frieman, Matthew

    Current opinion in virology

    2014  Volume 6, Page(s) 76–77

    MeSH term(s) Animals ; Host-Pathogen Interactions ; Humans ; Virus Diseases/etiology ; Virus Diseases/virology ; Virus Physiological Phenomena
    Keywords covid19
    Language English
    Publishing date 2014-06-02
    Publishing country Netherlands
    Document type Introductory Journal Article
    ZDB-ID 2611378-8
    ISSN 1879-6265 ; 1879-6257
    ISSN (online) 1879-6265
    ISSN 1879-6257
    DOI 10.1016/j.coviro.2014.05.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: 2',3' cyclic-nucleotide 3'-phosphodiesterase (CNP) inhibits SARS-CoV-2 virion assembly by blocking infection-induced mitochondria depolarization

    Logue, James / Melville, Victoria / Ardanuy, Jeremy / Frieman, Matthew

    bioRxiv

    Abstract: The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world9s healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus ... ...

    Abstract The COVID-19 pandemic has claimed over 6.5 million lives worldwide and continues to have lasting impacts on the world9s healthcare and economic systems. Several approved and emergency authorized therapeutics that inhibit early stages of the virus replication cycle have been developed however, effective late-stage therapeutical targets have yet to be identified. To that end, our lab identified 29,39 cyclic-nucleotide 39-phosphodiesterase (CNP) as a late-stage inhibitor of SARS-CoV-2 replication. We show that CNP inhibits the generation of new SARS-CoV-2 virions, reducing intracellular titers by over 10-fold without inhibiting viral structural protein translation. Additionally, we show that targeting of CNP to mitochondria is necessary for inhibition, implicating CNP9s proposed role as an inhibitor of the mitochondrial permeabilization transition pore as the mechanism of virion assembly inhibition. We also demonstrate that adenovirus transduction of a dually over-expressing virus expressing human ACE2, in cis with either CNP or eGFP inhibits SARS-CoV-2 titers to undetectable levels in lungs of mice. Collectively, this work shows the potential of CNP to be a new SARS-CoV-2 antiviral target.
    Keywords covid19
    Language English
    Publishing date 2023-06-09
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2023.06.09.544327
    Database COVID19

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  8. Article ; Online: Pyronaridine tetraphosphate is an efficacious antiviral and anti-inflammatory active against multiple highly pathogenic coronaviruses.

    Ardanuy, Jeremy / Johnson, Robert / Dillen, Carly / Taylor, Louis / Hammond, Holly / Weston, Stuart / Frieman, Matthew

    mBio

    2023  Volume 14, Issue 5, Page(s) e0158723

    Abstract: Importance: Pyronaridine tetraphosphate is on the WHO Essential Medicine List for its importance as a widely available and safe treatment for malaria. We find that pyronaridine is a highly effective antiviral therapeutic across mouse models using ... ...

    Abstract Importance: Pyronaridine tetraphosphate is on the WHO Essential Medicine List for its importance as a widely available and safe treatment for malaria. We find that pyronaridine is a highly effective antiviral therapeutic across mouse models using multiple variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and the highly pathogenic viruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus responsible for previous coronavirus outbreaks. Additionally, we find that pyronaridine additively combines with current COVID-19 treatments such as nirmatrelvir (protease inhibitor in Paxlovid) and molnupiravir to further inhibit SARS-CoV-2 infections. There are many antiviral compounds that demonstrate efficacy in cellular models, but few that show this level of impact in multiple mouse models and represent a promising therapeutic for the current coronavirus pandemic as well as future outbreaks as well.
    MeSH term(s) Mice ; Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Naphthyridines/pharmacology ; COVID-19 ; Middle East Respiratory Syndrome Coronavirus ; SARS-CoV-2
    Chemical Substances pyronaridine (TD3P7Q3SG6) ; Antiviral Agents ; Naphthyridines
    Language English
    Publishing date 2023-08-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.01587-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Association of Nirmatrelvir/Ritonavir Treatment and COVID-19-Neutralizing Antibody Titers in a Longitudinal Health Care Worker Cohort.

    Decker, Slade / Xiao, Shaoming / Dillen, Carly / Schumacher, Christina M / Milstone, Aaron M / Frieman, Matthew / Debes, Amanda K

    Open forum infectious diseases

    2024  Volume 11, Issue 2, Page(s) ofad625

    Abstract: Nirmatrelvir/ritonavir (NMV/r) is used for the treatment of coronavirus disease 2019 (COVID-19) infection. However, rebound COVID-19 infections can occur after taking NMV/r. We examined neutralizing antibodies to the severe acute respiratory syndrome ... ...

    Abstract Nirmatrelvir/ritonavir (NMV/r) is used for the treatment of coronavirus disease 2019 (COVID-19) infection. However, rebound COVID-19 infections can occur after taking NMV/r. We examined neutralizing antibodies to the severe acute respiratory syndrome coronavirus 2 spike protein before and after infection in people who did and did not take NMV/r to determine if NMV/r impedes the humoral immune response.
    Language English
    Publishing date 2024-02-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2757767-3
    ISSN 2328-8957
    ISSN 2328-8957
    DOI 10.1093/ofid/ofad625
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Insights from nanomedicine into chloroquine efficacy against COVID-19.

    Hu, Tony Y / Frieman, Matthew / Wolfram, Joy

    Nature nanotechnology

    2020  Volume 15, Issue 4, Page(s) 247–249

    MeSH term(s) Antiviral Agents/pharmacokinetics ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Betacoronavirus ; COVID-19 ; Chloroquine/pharmacokinetics ; Chloroquine/pharmacology ; Chloroquine/therapeutic use ; Coronavirus Infections/drug therapy ; Endocytosis/drug effects ; Humans ; Hydrogen-Ion Concentration ; Hydroxychloroquine/pharmacokinetics ; Hydroxychloroquine/pharmacology ; Hydroxychloroquine/therapeutic use ; Inflammation ; Nanomedicine ; Nanoparticles ; Pandemics ; Pneumonia, Viral/drug therapy ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/drug effects ; Spike Glycoprotein, Coronavirus/metabolism ; Virion/drug effects ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Hydroxychloroquine (4QWG6N8QKH) ; Chloroquine (886U3H6UFF)
    Keywords covid19
    Language English
    Publishing date 2020-03-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2254964-X
    ISSN 1748-3395 ; 1748-3387
    ISSN (online) 1748-3395
    ISSN 1748-3387
    DOI 10.1038/s41565-020-0674-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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