当前位置： SCI文献检索 > NATURE期刊下所有文献 > Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

Abstract：

:The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

journal_name

Nature

journal_title

Nature

authors

Warren TK,Jordan R,Lo MK,Ray AS,Mackman RL,Soloveva V,Siegel D,Perron M,Bannister R,Hui HC,Larson N,Strickley R,Wells J,Stuthman KS,Van Tongeren SA,Garza NL,Donnelly G,Shurtleff AC,Retterer CJ,Gharaibeh D,Zamani R

doi

10.1038/nature17180

subject

Has Abstract

pub_date

2016-03-17 00:00:00

pages

381-5

issue

7594

eissn

0028-0836

issn

1476-4687

pii

nature17180

journal_volume

531

pub_type

杂志文章

相关文献

NATURE文献大全
  • Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring.

    abstract：:Maternal immune activation (MIA) contributes to behavioural abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing autism spectrum disorder. In p...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature23910

    authors： Kim S,Kim H,Yim YS,Ha S,Atarashi K,Tan TG,Longman RS,Honda K,Littman DR,Choi GB,Huh JR

    更新日期：2017-09-28 00:00:00

  • Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers.

    abstract：:The peptide GsMTx4, isolated from the venom of the tarantula Grammostola spatulata, is a selective inhibitor of stretch-activated cation channels (SACs). The mechanism of inhibition remains unknown; but both GsMTx4 and its enantiomer, enGsMTx4, modify the gating of SACs, thus violating a trademark of the traditional l...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature02743

    authors： Suchyna TM,Tape SE,Koeppe RE 2nd,Andersen OS,Sachs F,Gottlieb PA

    更新日期：2004-07-08 00:00:00

  • Satellite-based estimates of groundwater depletion in India.

    abstract：:Groundwater is a primary source of fresh water in many parts of the world. Some regions are becoming overly dependent on it, consuming groundwater faster than it is naturally replenished and causing water tables to decline unremittingly. Indirect evidence suggests that this is the case in northwest India, but there ha...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature08238

    authors： Rodell M,Velicogna I,Famiglietti JS

    更新日期：2009-08-20 00:00:00

  • Keeping time with the human genome.

    abstract：:The cloning and characterization of 'clock gene' families has advanced our understanding of the molecular control of the mammalian circadian clock. We have analysed the human genome for additional relatives, and identified new candidate genes that may expand our knowledge of the molecular workings of the circadian clo...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/35057006

    authors： Clayton JD,Kyriacou CP,Reppert SM

    更新日期：2001-02-15 00:00:00

  • Testing the genetics underlying the co-evolution of mate choice and ornament in the wild.

    abstract：:One of the most debated questions in evolutionary biology is whether female choice of males with exaggerated sexual displays can evolve as a correlated response to selection acting on genes coding for male attractiveness or high overall viability. To date, empirical studies have provided support for parts of this scen...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature04564

    authors： Qvarnström A,Brommer JE,Gustafsson L

    更新日期：2006-05-04 00:00:00

  • Radiation-pressure mixing of large dust grains in protoplanetary disks.

    abstract：:Dusty disks around young stars are formed out of interstellar dust that consists of amorphous, submicrometre grains. Yet the grains found in comets and meteorites, and traced in the spectra of young stars, include large crystalline grains that must have undergone annealing or condensation at temperatures in excess of ...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature08032

    authors： Vinković D

    更新日期：2009-05-14 00:00:00

  • Chinese effort to clone gene-edited monkeys kicks off.

    abstract：: ...

    journal_title：Nature

    pub_type： 新闻

    doi：10.1038/d41586-019-00292-w

    authors： Cyranoski D

    更新日期：2019-02-01 00:00:00

  • High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy.

    abstract：:An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease. Recent studies of the Parkinson's disease associated genes PINK1 (ref. 2) and parkin (PARK2, ref. 3) indicate that they may act in a quality contr...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature12748

    authors： Hasson SA,Kane LA,Yamano K,Huang CH,Sliter DA,Buehler E,Wang C,Heman-Ackah SM,Hessa T,Guha R,Martin SE,Youle RJ

    更新日期：2013-12-12 00:00:00

  • 4S oop RNA is a leader sequence for the immunity-establishment transcription in coliphage lambda.

    abstract：:oop RNA, which is initiated at the po promoter and is 81 nucleotides long, can function as a leader sequence for the lambda immunity establishment transcription, previously believed to originate at a special promoter pre located in the y region. Thus, oop RNA seems to have a dual role, either favouring the lytic cycle...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/262112a0

    authors： Honigman A,Hu SL,Chase R,Szybalski W

    更新日期：1976-07-08 00:00:00

  • Bidirectional movement of actin filaments along tracks of myosin heads.

    abstract：:It is well established that muscle contraction results from the relative sliding of actin and myosin filaments. Both filaments have definite polarities and well-ordered structures. Thick filaments, however, are not vital for supporting movement in vitro. Previously we have demonstrated that actin filaments can move co...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/341154a0

    authors： Toyoshima YY,Toyoshima C,Spudich JA

    更新日期：1989-09-14 00:00:00

  • A 61-million-person experiment in social influence and political mobilization.

    abstract：:Human behaviour is thought to spread through face-to-face social networks, but it is difficult to identify social influence effects in observational studies, and it is unknown whether online social networks operate in the same way. Here we report results from a randomized controlled trial of political mobilization mes...

    journal_title：Nature

    pub_type： 杂志文章,随机对照试验

    doi：10.1038/nature11421

    authors： Bond RM,Fariss CJ,Jones JJ,Kramer AD,Marlow C,Settle JE,Fowler JH

    更新日期：2012-09-13 00:00:00

  • A spectrograph for exoplanet observations calibrated at the centimetre-per-second level.

    abstract：:The best spectrographs are limited in stability by their calibration light source. Laser frequency combs are the ideal calibrators for astronomical spectrographs. They emit a spectrum of lines that are equally spaced in frequency and that are as accurate and stable as the atomic clock relative to which the comb is sta...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature11092

    authors： Wilken T,Curto GL,Probst RA,Steinmetz T,Manescau A,Pasquini L,González Hernández JI,Rebolo R,Hänsch TW,Udem T,Holzwarth R

    更新日期：2012-05-30 00:00:00

  • Gulf Stream density structure and transport during the past millennium.

    abstract：:The Gulf Stream transports approximately 31 Sv (1 Sv = 10(6) m(3) s(-1)) of water and 1.3 x 10(15) W of heat into the North Atlantic ocean. The possibility of abrupt changes in Gulf Stream heat transport is one of the key uncertainties in predictions of climate change for the coming centuries. Given the limited length...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature05277

    authors： Lund DC,Lynch-Stieglitz J,Curry WB

    更新日期：2006-11-30 00:00:00

  • AMD1 mRNA employs ribosome stalling as a mechanism for molecular memory formation.

    abstract：:In addition to acting as template for protein synthesis, messenger RNA (mRNA) often contains sensory sequence elements that regulate this process. Here we report a new mechanism that limits the number of complete protein molecules that can be synthesized from a single mRNA molecule of the human AMD1 gene encoding aden...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature25174

    authors： Yordanova MM,Loughran G,Zhdanov AV,Mariotti M,Kiniry SJ,O'Connor PBF,Andreev DE,Tzani I,Saffert P,Michel AM,Gladyshev VN,Papkovsky DB,Atkins JF,Baranov PV

    更新日期：2018-01-18 00:00:00

  • Vascular respiratory uncoupling increases blood pressure and atherosclerosis.

    abstract：:The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature03527

    authors： Bernal-Mizrachi C,Gates AC,Weng S,Imamura T,Knutsen RH,DeSantis P,Coleman T,Townsend RR,Muglia LJ,Semenkovich CF

    更新日期：2005-05-26 00:00:00

  • Structure of the Vdelta domain of a human gammadelta T-cell antigen receptor.

    abstract：:Antigen recognition by T lymphocytes is mediated by cell-surface glycoproteins known as T-cell antigen receptors (TCRs). These are composed of alpha and beta, or gamma and delta, polypeptide chains with variable (V) and constant (C) regions. In contrast to alphabeta TCRs, which recognize antigen only as peptide fragme...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/35172

    authors： Li H,Lebedeva MI,Llera AS,Fields BA,Brenner MB,Mariuzza RA

    更新日期：1998-01-29 00:00:00

  • Conservation of hippocampal memory function in rats and humans.

    abstract：:The hippocampus is critical to declarative memory in humans. This kind of memory involves associations among items or events that can be accessed flexibly to guide memory expression in various and even new situations. In animals, there has been controversy about whether the hippocampus is specialized for spatial memor...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/379255a0

    authors： Bunsey M,Eichenbaum H

    更新日期：1996-01-18 00:00:00

  • A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression.

    abstract：:Transcriptional repression by nuclear receptors has been correlated to binding of the putative co-repressor, N-CoR. A complex has been identified that contains N-CoR, the Mad presumptive co-repressor mSin3, and the histone deacetylase mRPD3, and which is required for both nuclear receptor- and Mad-dependent repression...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/387043a0

    authors： Heinzel T,Lavinsky RM,Mullen TM,Söderstrom M,Laherty CD,Torchia J,Yang WM,Brard G,Ngo SD,Davie JR,Seto E,Eisenman RN,Rose DW,Glass CK,Rosenfeld MG

    更新日期：1997-05-01 00:00:00

  • Optical addressing of an individual erbium ion in silicon.

    abstract：:The detection of electron spins associated with single defects in solids is a critical operation for a range of quantum information and measurement applications under development. So far, it has been accomplished for only two defect centres in crystalline solids: phosphorus dopants in silicon, for which electrical rea...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature12081

    authors： Yin C,Rancic M,de Boo GG,Stavrias N,McCallum JC,Sellars MJ,Rogge S

    更新日期：2013-05-02 00:00:00

  • Atomic-scale images of charge ordering in a mixed-valence manganite.

    abstract：:Transition-metal perovskite oxides exhibit a wide range of extraordinary but imperfectly understood phenomena. The best known examples are high-temperature superconductivity in copper oxides, and colossal magnetoresistance in manganese oxides ('manganites'). All of these materials undergo a range of order-disorder tra...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/416518a

    authors： Renner Ch,Aeppli G,Kim BG,Soh YA,Cheong SW

    更新日期：2002-04-04 00:00:00

  • Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.

    abstract：:Many voltage-dependent K+ channels open when the membrane is depolarized and then rapidly close by a process called inactivation. Neurons use inactivating K+ channels to modulate their firing frequency. In Shaker-type K+ channels, the inactivation gate, which is responsible for the closing of the channel, is formed by...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/35079500

    authors： Zhou M,Morais-Cabral JH,Mann S,MacKinnon R

    更新日期：2001-06-07 00:00:00

  • Human cell-surface glycoprotein with unusual properties.

    abstract：:We report here the identification of human cell-surface glycoprotein with unusual and interesting properties. We initially detected this glycoprotein on the surface of cultured human haematopoietic cell lines by means of a monoclonal antibody. Although it is expressed on all cultured human haematopoietic cell lines te...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/286888a0

    authors： Omary MB,Trowbridge IS,Minowada J

    更新日期：1980-08-28 00:00:00

  • Molecular understanding of sulphuric acid-amine particle nucleation in the atmosphere.

    abstract：:Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei. Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes. At...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature12663

    authors： Almeida J,Schobesberger S,Kürten A,Ortega IK,Kupiainen-Määttä O,Praplan AP,Adamov A,Amorim A,Bianchi F,Breitenlechner M,David A,Dommen J,Donahue NM,Downard A,Dunne E,Duplissy J,Ehrhart S,Flagan RC,Franchin A,Guida R

    更新日期：2013-10-17 00:00:00

  • Modern freshwater microbialite analogues for ancient dendritic reef structures.

    abstract：:Microbialites are organosedimentary structures that can be constructed by a variety of metabolically distinct taxa. Consequently, microbialite structures abound in the fossil record, although the exact nature of the biogeochemical processes that produced them is often unknown. One such class of ancient calcareous stru...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/35036579

    authors： Laval B,Cady SL,Pollack JC,McKay CP,Bird JS,Grotzinger JP,Ford DC,Bohm HR

    更新日期：2000-10-05 00:00:00

  • Structural basis for action by diverse antidepressants on biogenic amine transporters.

    abstract：:The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature12648

    authors： Wang H,Goehring A,Wang KH,Penmatsa A,Ressler R,Gouaux E

    更新日期：2013-11-07 00:00:00

  • Decay characteristics of HIV-1-infected compartments during combination therapy.

    abstract：:Analysis of changes in viral load after initiation of treatment with potent antiretroviral agents has provided substantial insight into the dynamics of human immunodeficiency virus type 1 (HIV-1). The concentration of HIV-1 in plasma drops by approximately 99% in the first two weeks of treatment owing to the rapid eli...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/387188a0

    authors： Perelson AS,Essunger P,Cao Y,Vesanen M,Hurley A,Saksela K,Markowitz M,Ho DD

    更新日期：1997-05-08 00:00:00

  • Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1.

    abstract：:Polycomb and trithorax group (PcG and trxG) proteins maintain silent and active transcriptional states, respectively, throughout development. In Drosophila, PcG and trxG proteins associate with DNA regions named Polycomb and trithorax response elements (PRE and TRE), but the mechanisms of recruitment are unknown. We p...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature03386

    authors： Déjardin J,Rappailles A,Cuvier O,Grimaud C,Decoville M,Locker D,Cavalli G

    更新日期：2005-03-24 00:00:00

  • Direct human influence on atmospheric CO2 seasonality from increased cropland productivity.

    abstract：:Ground- and aircraft-based measurements show that the seasonal amplitude of Northern Hemisphere atmospheric carbon dioxide (CO2) concentrations has increased by as much as 50 per cent over the past 50 years. This increase has been linked to changes in temperate, boreal and arctic ecosystem properties and processes suc...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/nature13957

    authors： Gray JM,Frolking S,Kort EA,Ray DK,Kucharik CJ,Ramankutty N,Friedl MA

    更新日期：2014-11-20 00:00:00

  • Constraints on the composition of the Earth's core from ab initio calculations

    abstract：:Knowledge of the composition of the Earth's core is important for understanding its melting point and therefore the temperature at the inner-core boundary and the temperature profile of the core and mantle. In addition, the partitioning of light elements between solid and liquid, as the outer core freezes at the inner...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/35012056

    authors： Alfe D,Gillan MJ,Price GD

    更新日期：2000-05-11 00:00:00

  • Signal clipping by the rod output synapse.

    abstract：:The properties of synapses between retinal neurons make an essential contribution to early visual processing. Light produces a graded hyperpolarization in photoreceptors, up to 25 mV in amplitude, and it is conventionally assumed that all of this response range is available for coding visual information. We report her...

    journal_title：Nature

    pub_type： 杂志文章

    doi：10.1038/328522a0

    authors： Attwell D,Borges S,Wu SM,Wilson M

    更新日期：1987-08-06 00:00:00