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  1. Article ; Online: Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases.

    Meganck, Rita M / Baric, Ralph S

    Nature medicine

    2021  Volume 27, Issue 3, Page(s) 401–410

    Abstract: The twenty-first century has already recorded more than ten major epidemic or pandemic virus emergence events, including the ongoing and devastating coronavirus disease 2019 (COVID-19) pandemic. As viral disease emergence is expected to accelerate, these ...

    Abstract The twenty-first century has already recorded more than ten major epidemic or pandemic virus emergence events, including the ongoing and devastating coronavirus disease 2019 (COVID-19) pandemic. As viral disease emergence is expected to accelerate, these data dictate a need for proactive approaches to develop broadly active family-specific and cross-family therapeutics for use in future disease outbreaks. Emphasis should focus not only on the development of broad-spectrum small-molecule and antibody direct-acting antivirals, but also on host-factor therapeutics, including repurposing previously approved or in-pipeline drugs. Another new class of therapeutics with great antiviral therapeutic potential is RNA-based therapeutics. Rather than only focusing on known risks, dedicated efforts must be made toward pre-emptive research focused on outbreak-prone virus families, ultimately offering a strategy to shorten the gap between outbreak and response. Emphasis should also focus on orally available drugs for outpatient use, if possible, and on identifying combination therapies that combat viral and immune-mediated pathologies, extend the effectiveness of therapeutic windows and reduce drug resistance. While such an undertaking will require new vision, dedicated funding and private, federal and academic partnerships, this approach offers hope that global populations need never experience future pandemics such as COVID-19.
    MeSH term(s) Antiviral Agents/therapeutic use ; COVID-19/epidemiology ; Communicable Diseases, Emerging/therapy ; Drug Development/methods ; Drug Development/trends ; Drug Repositioning ; History, 21st Century ; Humans ; Inventions/trends ; Pandemics ; SARS-CoV-2 ; Therapies, Investigational/methods ; Therapies, Investigational/trends ; Virus Diseases/therapy ; COVID-19 Drug Treatment
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2021-03-15
    Publishing country United States
    Document type Historical Article ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1220066-9
    ISSN 1546-170X ; 1078-8956
    ISSN (online) 1546-170X
    ISSN 1078-8956
    DOI 10.1038/s41591-021-01282-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Erratum: Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation.

    Holmquist, Chris E / He, Wenxia / Meganck, Rita M / Marzluff, William F

    RNA (New York, N.Y.)

    2023  Volume 29, Issue 6, Page(s) 862

    Language English
    Publishing date 2023-05-16
    Publishing country United States
    Document type Journal Article ; Published Erratum
    ZDB-ID 1241540-6
    ISSN 1469-9001 ; 1355-8382
    ISSN (online) 1469-9001
    ISSN 1355-8382
    DOI 10.1261/rna.079667.123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Knockouts of TUT7 and 3'hExo show that they cooperate in histone mRNA maintenance and degradation.

    Holmquist, Chris E / He, Wenxia / Meganck, Rita M / Marzluff, William F

    RNA (New York, N.Y.)

    2022  Volume 28, Issue 11, Page(s) 1519–1533

    Abstract: Metazoan histone mRNAs are the only cellular eukaryotic mRNAs that are not polyadenylated, ending instead in a conserved stem-loop. SLBP is bound to the 3' end of histone mRNAs and is required for translation of histone mRNA. The expression of histone ... ...

    Abstract Metazoan histone mRNAs are the only cellular eukaryotic mRNAs that are not polyadenylated, ending instead in a conserved stem-loop. SLBP is bound to the 3' end of histone mRNAs and is required for translation of histone mRNA. The expression of histone mRNAs is tightly cell-cycle regulated. A major regulatory step is rapid degradation of histone mRNA at the end of S-phase or when DNA synthesis is inhibited in S-phase. 3'hExo, a 3' to 5' exonuclease, binds to the SLBP/SL complex and trims histone mRNA to 3 nt after the stem-loop. Together with a terminal uridyl transferase, 3'hExo maintains the length of the histone mRNA during S-phase. 3'hExo is essential for initiating histone mRNA degradation on polyribosomes, initiating degradation into the 3' side of the stem-loop. There is extensive uridylation of degradation intermediates in the 3' side of the stem when histone mRNA is degraded. Here, we knocked out TUT7 and 3'hExo and we show that both modification of histone mRNA during S-phase and degradation of histone mRNA involve the interaction of 3'hExo, and a specific TUTase, TENT3B (TUT7, ZCCHC6). Knockout of 3'hExo prevents the initiation of 3' to 5' degradation, stabilizing histone mRNA, whereas knockout of TUT7 prevents uridylation of the mRNA degradation intermediates, slowing the rate of degradation. In synchronized 3'hExo KO cells, histone mRNA degradation is delayed, but the histone mRNA is degraded prior to mitosis by a different pathway.
    MeSH term(s) Animals ; Humans ; Histones/genetics ; Histones/metabolism ; Menogaril ; HeLa Cells ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; mRNA Cleavage and Polyadenylation Factors/metabolism
    Chemical Substances Histones ; Menogaril (8JSV4O30HQ) ; RNA, Messenger ; mRNA Cleavage and Polyadenylation Factors
    Language English
    Publishing date 2022-08-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1241540-6
    ISSN 1469-9001 ; 1355-8382
    ISSN (online) 1469-9001
    ISSN 1355-8382
    DOI 10.1261/rna.079233.122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses.

    Tse, Longping V / Meganck, Rita M / Graham, Rachel L / Baric, Ralph S

    Frontiers in microbiology

    2020  Volume 11, Page(s) 658

    Abstract: Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence ...

    Abstract Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence of highly pathogenic CoVs in human. However, given the diverse nature of CoVs and our close interactions with wild, domestic and companion animals, the next epidemic zoonotic CoV could resist the existing vaccines and antivirals developed, which are primarily focused on Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS CoV). In late 2019, the novel CoV (SARS-CoV-2) emerged in Wuhan, China, causing global public health concern. In this review, we will summarize the key advancements of current vaccines and antivirals against SARS-CoV and MERS-CoV as well as discuss the challenge and opportunity in the current SARS-CoV-2 crisis. At the end, we advocate the development of a "plug-and-play" platform technologies that could allow quick manufacturing and administration of broad-spectrum countermeasures in an outbreak setting. We will discuss the potential of AAV-based gene therapy technology for
    Keywords covid19
    Language English
    Publishing date 2020-04-24
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2020.00658
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Lifetime of ground conformational state determines the activity of structured RNA.

    Thompson, Rhese D / Carbaugh, Derek L / Nielsen, Joshua R / Witt, Ciara M / Meganck, Rita M / Rangadurai, Atul / Zhao, Bo / Bonin, Jeffrey P / Nicely, Nathan I / Marzluff, William F / Frank, Aaron T / Lazear, Helen M / Zhang, Qi

    Research square

    2023  

    Abstract: Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the 3D structure, the lifetime of a ground conformational ... ...

    Abstract Biomolecules continually sample alternative conformations. Consequently, even the most energetically favored ground conformational state has a finite lifetime. Here, we show that, in addition to the 3D structure, the lifetime of a ground conformational state determines its biological activity. Using hydrogen-deuterium exchange nuclear magnetic resonance spectroscopy, we found that Zika virus exoribonuclease-resistant RNA (xrRNA) encodes a ground conformational state with a lifetime that is ~10
    Language English
    Publishing date 2023-05-26
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-2879957/v1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Evolution of a functionally intact but antigenically distinct DENV fusion loop.

    Meganck, Rita M / Zhu, Deanna / Dong, Stephanie / Snoderly-Foster, Lisa J / Dalben, Yago R / Thiono, Devina / White, Laura J / DeSilva, Arivianda M / Baric, Ralph S / Tse, Longping V

    eLife

    2023  Volume 12

    Abstract: A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety ... ...

    Abstract A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. Antibody-dependent enhancement is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL), which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2)-infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live-attenuated DENV vaccines suitable for naïve individuals and children.
    MeSH term(s) Animals ; Antibodies, Monoclonal ; Cross Reactions ; Culicidae ; Engineering ; Vaccines
    Chemical Substances Antibodies, Monoclonal ; Vaccines
    Language English
    Publishing date 2023-09-19
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.87555
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Evolution of a Functionally Intact but Antigenically Distinct DENV Fusion Loop.

    Meganck, Rita M / Zhu, Deanna / Dong, Stephanie / Snoderly-Foster, Lisa J / Dalben, Yago R / Thiono, Devina / White, Laura J / DeSilva, Aravinda M / Baric, Ralph S / Tse, Longping V

    bioRxiv : the preprint server for biology

    2023  

    Abstract: A hallmark of Dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety ... ...

    Abstract A hallmark of Dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. ADE is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL) which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4) infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2) infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live attenuated DENV vaccines suitable for naïve individuals and children.
    Language English
    Publishing date 2023-08-04
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.22.533803
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Dengue virus 4/2 envelope domain chimeric virus panel maps type-specific responses against dengue serotype 2.

    Zhu, Deanna R / Rajesh, Alecia J / Meganck, Rita M / Young, Ellen F / Munt, Jennifer E / Tse, Victor L / Yount, Boyd / Conrad, Helen / White, Laura / Henein, Sandra / DeSilva, Aravinda M / Baric, Ralph S

    mBio

    2023  Volume 14, Issue 5, Page(s) e0081823

    Abstract: Importance: The four dengue virus (DENV) serotypes infect several hundred million people each year. Although primary infection is generally mild, subsequent infection by differing serotypes increases the risk for symptomatic disease ranging from fever ... ...

    Abstract Importance: The four dengue virus (DENV) serotypes infect several hundred million people each year. Although primary infection is generally mild, subsequent infection by differing serotypes increases the risk for symptomatic disease ranging from fever to life-threatening shock. Despite the availability of licensed vaccines, a comprehensive understanding of antibodies that target the viral envelope protein and protect from infection remains incomplete. In this manuscript, we develop a panel of recombinant viruses that graft each envelope domain of DENV2 onto the DENV4 envelope glycoprotein, revealing protein interactions important for virus viability. Furthermore, we map neutralizing antibody responses after primary DENV2 natural infection and a human challenge model to distinct domains on the viral envelope protein. The panel of recombinant viruses provides a new tool for dissecting the E domain-specific targeting of protective antibody responses, informing future DENV vaccine design.
    MeSH term(s) Humans ; Dengue Virus ; Dengue ; Antibodies, Viral ; Viral Envelope Proteins/genetics ; Serogroup ; Antibodies, Neutralizing
    Chemical Substances Antibodies, Viral ; Viral Envelope Proteins ; Antibodies, Neutralizing
    Language English
    Publishing date 2023-10-06
    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.00818-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Mapping and Engineering Functional Domains of the Assembly-Activating Protein of Adeno-associated Viruses.

    Tse, Longping V / Moller-Tank, Sven / Meganck, Rita M / Asokan, Aravind

    Journal of virology

    2018  Volume 92, Issue 14

    Abstract: Adeno-associated viruses (AAVs) encode a unique assembly-activating protein (AAP) within their genomes that is essential for capsid assembly. Studies to date have focused on establishing the role of AAP as a chaperone that mediates the stability, ... ...

    Abstract Adeno-associated viruses (AAVs) encode a unique assembly-activating protein (AAP) within their genomes that is essential for capsid assembly. Studies to date have focused on establishing the role of AAP as a chaperone that mediates the stability, nucleolar transport, and assembly of AAV capsid proteins. Here, we map structure-function correlates of AAP using secondary structure analysis, followed by deletion and substitutional mutagenesis of specific domains, namely, the N-terminal hydrophobic region (HR), conserved core (CC), proline-rich region (PRR), threonine/serine-rich region (T/S), and basic region (BR). First, we establish that the centrally located PRR and T/S are flexible linker domains that can either be deleted completely or replaced by heterologous functional domains that enable ancillary functions such as fluorescent imaging or increased AAP stability. We also demonstrate that the C-terminal BR domains can be substituted with heterologous nuclear or nucleolar localization sequences that display various abilities to support AAV capsid assembly. Further, by replacing the BR domain with immunoglobulin (IgG) Fc domains, we assessed AAP complexation with AAV capsid subunits and demonstrate that the hydrophobic region (HR) and the conserved core (CC) in the AAP N terminus are the sole determinants for viral protein (VP) recognition. However, VP recognition alone is not sufficient for capsid assembly. Our study sheds light on the modular structure-function correlates of AAP and provides multiple approaches to engineer AAP that might prove useful toward understanding and controlling AAV capsid assembly.
    MeSH term(s) Capsid Proteins/chemistry ; Capsid Proteins/metabolism ; Cell Nucleus/metabolism ; Dependovirus/physiology ; HeLa Cells ; Humans ; Nuclear Localization Signals ; Parvoviridae Infections/virology ; Protein Conformation ; Protein Domains ; Protein Stability ; Protein Transport ; Virion ; Virus Assembly
    Chemical Substances Capsid Proteins ; Nuclear Localization Signals
    Language English
    Publishing date 2018-06-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.00393-18
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: The Current and Future State of Vaccines, Antivirals and Gene Therapies Against Emerging Coronaviruses

    Tse, Longping V. / Meganck, Rita M. / Graham, Rachel L. / Baric, Ralph S.

    Front. Microbiol.

    Abstract: Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence ...

    Abstract Emerging coronaviruses (CoV) are constant global public health threats to society. Multiple ongoing clinical trials for vaccines and antivirals against CoVs showcase the availability of medical interventions to both prevent and treat the future emergence of highly pathogenic CoVs in human. However, given the diverse nature of CoVs and our close interactions with wild, domestic and companion animals, the next epidemic zoonotic CoV could resist the existing vaccines and antivirals developed, which are primarily focused on Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS CoV). In late 2019, the novel CoV (SARS-CoV-2) emerged in Wuhan, China, causing global public health concern. In this review, we will summarize the key advancements of current vaccines and antivirals against SARS-CoV and MERS-CoV as well as discuss the challenge and opportunity in the current SARS-CoV-2 crisis. At the end, we advocate the development of a “plug-and-play” platform technologies that could allow quick manufacturing and administration of broad-spectrum countermeasures in an outbreak setting. We will discuss the potential of AAV-based gene therapy technology for in vivo therapeutic antibody delivery to combat SARS-CoV-2 outbreak and the future emergence of severe CoVs.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #853956
    Database COVID19

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