Potent inhibition of arenavirus infection by a novel fusion inhibitor.
Potent inhibition of arenavirus infection by a novel fusion inhibitor.
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新型融合抑制剂对沙粒病毒感染的有效抑制。
DOI：
10.1016/j.antiviral.2021.105125
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发表时间：
2021-09
影响因子：
7.6
通讯作者：
Henkel G
中科院分区：
文献类型：
--
作者：
Gowen BB;Naik S;Westover JB;Brown ER;Gantla VR;Fetsko A;Dagley AL;Blotter DJ;Anderson N;McCormack K;Henkel G
几种沙粒病毒，包括非洲的拉沙病毒和卢霍病毒以及美洲的五种新世界沙粒病毒（NWA），会引起危及生命的病毒性出血热。在没有获得许可的抗病毒疗法的情况下，这些病毒构成重大的公共卫生风险。包膜糖蛋白复合物（GPC）通过病毒和宿主内体膜的pH依赖性融合介导沙粒病毒进入。因此，它被认为是小分子融合抑制剂的可行靶标。在这里，我们报告了新型广谱沙粒病毒融合抑制剂ARN-75039和ARN-75041的抗病毒活性和临床前开发。在Tacaribe病毒（TCRV）假型和天然病毒测定中，ARN化合物在低至亚纳摩尔范围内具有活性，选择性指数超过1000。口服给药化合物的药代动力学分析显示，在小鼠中延长的半衰期支持每日一次给药，并且化合物在最高测试剂量100 mg/kg下耐受良好。在一项概念验证性预防有效性研究中，10和35 mg/kg剂量的任一化合物均显著改善了生存结局，并有效抑制了血清和各种组织中的TCRV复制。此外，与接受利巴韦林或安慰剂的存活小鼠相反，用ARN-75039或ARN-75041治疗的动物治愈了TCRV感染。在一项ARN-75039的随访研究中，在疾病发作前停止治疗的情况下，显示出令人印象深刻的治疗效果。综上所述，这些数据强烈支持ARN-75039作为治疗严重沙粒病毒疾病的候选治疗剂的持续开发。
Several arenaviruses, including Lassa and Lujo viruses in Africa and five New World arenavirus (NWA) species in the Americas, cause life-threatening viral hemorrhagic fevers. In the absence of licensed antiviral therapies, these viruses pose a significant public health risk. The envelope glycoprotein complex (GPC) mediates arenavirus entry through a pH-dependent fusion of the viral and host endosomal membranes. It thus is recognized as a viable target for small-molecule fusion inhibitors. Here, we report on the antiviral activity and pre-clinical development of the novel broad-spectrum arenavirus fusion inhibitors, ARN-75039 and ARN-75041. In Tacaribe virus (TCRV) pseudotyped and native virus assays, the ARN compounds were active in the low to sub-nanomolar range with selectivity indices exceeding 1000. Pharmacokinetic analysis of the orally administered compounds revealed an extended half-life in mice supporting once-daily dosing, and the compounds were well tolerated at the highest tested dose of 100 mg/kg. In a proof-of-concept prophylactic efficacy study, doses of 10 and 35 mg/kg of either compound dramatically improved survival outcome and potently inhibited TCRV replication in serum and various tissues. Additionally, in contrast to surviving mice that received ribavirin or placebo, animals treated with ARN-75039 or ARN-75041 were cured of TCRV infection. In a follow-up study with ARN-75039, impressive therapeutic efficacy was demonstrated under conditions where treatment was withheld until after the onset of disease. Taken together, the data strongly support the continued development of ARN-75039 as a candidate therapeutic for the treatment of severe arenaviral diseases.
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影响因子：
6.7
作者：
Abraham, Jonathan;Kwong, Jo Ann;Choe, Hyeryun
通讯作者：
Choe, Hyeryun
影响因子：
4.8
作者：
Sefing EJ;Wong MH;Larson DP;Hurst BL;Van Wettere AJ;Schneller SW;Gowen BB
通讯作者：
Gowen BB
DOI：
10.3390/v4010083
发表时间：
2012-01
期刊：
Viruses
影响因子：
--
作者：
Nunberg JH;York J
通讯作者：
York J
影响因子：
2.7
作者：
Plewe, Michael B.;Whitby, Landon R.;McCormack, Ken
通讯作者：
McCormack, Ken
影响因子：
7.6
作者：
Enria DA;Briggiler AM;Sánchez Z
通讯作者：
Sánchez Z