Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.
Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.
复制标题
广谱抗病毒GS-5734抑制流行病和人畜共患病毒。
DOI：
10.1126/scitranslmed.aal3653
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发表时间：
2017-06-28
影响因子：
17.1
通讯作者：
Baric RS
中科院分区：
文献类型：
--
作者：
Sheahan TP;Sims AC;Graham RL;Menachery VD;Gralinski LE;Case JB;Leist SR;Pyrc K;Feng JY;Trantcheva I;Bannister R;Park Y;Babusis D;Clarke MO;Mackman RL;Spahn JE;Palmiotti CA;Siegel D;Ray AS;Cihlar T;Jordan R;Denison MR;Baric RS
新出现的病毒感染很难控制，因为不同的成员周期性地进出人类和人畜共患宿主，使特定的抗病毒疗法和疫苗的开发复杂化。冠状病毒(CoV)具有迅速传播到新的宿主物种导致严重疾病的倾向。SARS-CoV和MERS-CoV相继出现，在全球免疫幼稚的人群中引发了严重的流行性呼吸道疾病。能够抑制冠状病毒感染的广谱疗法将解决眼下未得到满足的医疗需求，在治疗新出现的和地方性冠状病毒感染方面可能是无价的。在这里，我们展示了一种核苷酸前体药物GS-5734，目前正在临床开发用于治疗埃博拉病毒疾病，可以在多种体外系统中抑制SARS-CoV和MERS-CoV的复制，包括具有亚微摩尔IC50值的原代人呼吸道上皮细胞培养。GS-5734对原代人肺细胞中的BAT冠状病毒、流行前BAT冠状病毒和循环当代人类冠状病毒也有效，从而显示出广谱的抗冠状病毒活性。在SARS冠状病毒致病的小鼠模型中，预防性和早期治疗应用GS-5734显著降低了肺部病毒载量，改善了疾病的临床症状和呼吸功能。这些数据提供了大量证据表明，GS-5734可能被证明对中东地方性MERS-CoV、正在传播的人类CoV以及可能最重要的未来新出现的CoV有效。
Emerging viral infections are difficult to control as heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. SARS-CoV and MERS-CoV successively emerged causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. Here we show that a nucleotide prodrug GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat-CoVs, prepandemic bat-CoVs and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory functions. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and possibly most importantly, emerging CoV of the future.
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影响因子：
82.9
作者：
Menachery VD;Yount BL Jr;Debbink K;Agnihothram S;Gralinski LE;Plante JA;Graham RL;Scobey T;Ge XY;Donaldson EF;Randell SH;Lanzavecchia A;Marasco WA;Shi ZL;Baric RS
通讯作者：
Baric RS
DOI：
10.1038/nrmicro.2016.81
发表时间：
2016-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
de Wit E;van Doremalen N;Falzarano D;Munster VJ
通讯作者：
Munster VJ
影响因子：
6.4
作者：
Agnihothram S;Yount BL Jr;Donaldson EF;Huynh J;Menachery VD;Gralinski LE;Graham RL;Becker MM;Tomar S;Scobey TD;Osswald HL;Whitmore A;Gopal R;Ghosh AK;Mesecar A;Zambon M;Heise M;Denison MR;Baric RS
通讯作者：
Baric RS
影响因子：
3.7
作者：
Menachery, Vineet D.;Gralinski, Lisa E.;Ferris, Martin T.
通讯作者：
Ferris, Martin T.
影响因子：
5.4
作者：
Sims, AC;Baric, RS;Pickles, RJ
通讯作者：
Pickles, RJ