1,723,465 research outputs found
Block Card 5734 Winona Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Dwelling | 5734 Winona Street (Toledo, Ohio) | Ranch houses | Ann Acres (Toledo, Ohio) | Greenwood Area (Toledo, Ohio) | West Toledo Area (Toledo, Ohio
Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease
No full textABSTRACT
Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs
in vitro
and in a severe acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with GS-5734 have not reported resistance associated with GS-5734, nor do we understand the action of GS-5734 in wild-type (WT) proofreading CoVs. Here, we show that GS-5734 inhibits murine hepatitis virus (MHV) with similar 50% effective concentration values (EC
50
) as SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Passage of WT MHV in the presence of the GS-5734 parent nucleoside selected two mutations in the nsp12 polymerase at residues conserved across all CoVs that conferred up to 5.6-fold resistance to GS-5734, as determined by EC
50
. The resistant viruses were unable to compete with WT in direct coinfection passage in the absence of GS-5734. Introduction of the MHV resistance mutations into SARS-CoV resulted in the same
in vitro
resistance phenotype and attenuated SARS-CoV pathogenesis in a mouse model. Finally, we demonstrate that an MHV mutant lacking ExoN proofreading was significantly more sensitive to GS-5734. Combined, the results indicate that GS-5734 interferes with the nsp12 polymerase even in the setting of intact ExoN proofreading activity and that resistance can be overcome with increased, nontoxic concentrations of GS-5734, further supporting the development of GS-5734 as a broad-spectrum therapeutic to protect against contemporary and emerging CoVs.
IMPORTANCE
Coronaviruses (CoVs) cause severe human infections, but there are no approved antivirals to treat these infections. Development of nucleoside-based therapeutics for CoV infections has been hampered by the presence of a proofreading exoribonuclease. Here, we expand the known efficacy of the nucleotide prodrug remdesivir (GS-5734) to include a group β-2a CoV. Further, GS-5734 potently inhibits CoVs with intact proofreading. Following selection with the GS-5734 parent nucleoside, 2 amino acid substitutions in the nsp12 polymerase at residues that are identical across CoVs provide low-level resistance to GS-5734. The resistance mutations decrease viral fitness of MHV
in vitro
and attenuate pathogenesis in a SARS-CoV animal model of infection. Together, these studies define the target of GS-5734 activity and demonstrate that resistance is difficult to select, only partial, and impairs fitness and virulence of MHV and SARS-CoV, supporting further development of GS-5734 as a potential effective pan-CoV antiviral.
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Block Card 5734 St. Clement Court
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Colonial Revival Style | 5734 St. Clement Court (Toledo, Ohio) | Dwelling | St. Clement Court (Toledo, Ohio) | Trilby Area (Toledo, Ohio
Swift J1644+5734: the EVN view
No full textA small fraction of Tidal Disruption Events (TDE) produce relativistic jets, evidenced by their non-thermal X-ray spectra and transient radio emission. Here we present milliarcsecond-resolution imaging results on TDE J1644+5734 with the European VLBI Network (EVN). These provide a strong astrometric constraint on the average apparent jet velocity
βapp < 0.27, that constrains the intrinsic jet velocity for a given viewing angle
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses
No full textBroad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses in vitro and in vivo.</jats:p
GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses
No full textAbstractGS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern.</jats:p
Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys
No full textThese authors report the discovery of a small-molecule drug, GS-5734, which has antiviral activity against Ebola and other filoviruses, and is capable of providing post-exposure protection against Ebola virus in 100 of infected macaques tested. Now in clinical trials (http://go.nature.com/PEW2Oi), the drug targets the viral RNA-dependent RNA polymerase and is readily scalable for future outbreaks. GS-5734 is able to distribute to sanctuary sites for viral replication including the testes, eye and brain, offering the hope that this drug may also be able to clear recrudescent and persistent virus infection
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