Severe mammarenaviral disease in guinea pigs effectively treated by an orally bioavailable fusion inhibitor, alone or in combination with favipiravir.
Severe mammarenaviral disease in guinea pigs effectively treated by an orally bioavailable fusion inhibitor, alone or in combination with favipiravir.
复制标题
DOI：
10.1016/j.antiviral.2022.105444
复制
发表时间：
2022-12
影响因子：
7.6
通讯作者：
中科院分区：
文献类型：
--
作者：
包括Junín病毒在内的致病性新世界哺乳动物病毒S的感染可导致严重威胁生命的病毒性出血热综合征。在没有FDA许可的疫苗或抗病毒药物的情况下，这些病毒被认为是高度优先的病原体。哺乳动物病毒包膜糖蛋白复合体(GPC)介导病毒和细胞膜之间的pH依赖的融合，这是病毒进入所必需的，可能容易受到破坏这一过程的小分子抑制剂的影响。ARN-75039是一种有效的融合抑制剂，可用于细胞培养中的广泛假型和天然哺乳动物病毒以及小鼠的塔卡里贝病毒感染。在本研究中，我们在严格的豚鼠感染模型中评估了ARN-75039对致病性JUNV的作用。该化合物耐受性好，具有良好的药代动力学，支持豚鼠每日一次口服给药。重要的是，即使当ARN-75039被扣留到病毒挑战后6天，当疾病的临床症状开始发展时，也观察到对JUNV挑战的显著保护。我们还表明，ARN-75039与病毒聚合酶抑制剂法韦拉韦联合治疗，在体外产生了协同活性，并改善了JUNV攻击的豚鼠的生存结果。我们的发现支持ARN-75039继续发展成为治疗哺乳动物病毒性出血热的有吸引力的候选药物，包括与NWM感染相关的出血热。
Infections by pathogenic New World mammarenaviruses (NWM)s, including Junín virus (JUNV), can result in a severe life-threatening viral hemorrhagic fever syndrome. In the absence of FDA-licensed vaccines or antivirals, these viruses are considered high priority pathogens. The mammarenavirus envelope glycoprotein complex (GPC) mediates pH-dependent fusion between viral and cellular membranes, which is essential to viral entry and may be vulnerable to small-molecule inhibitors that disrupt this process. ARN-75039 is a potent fusion inhibitor of a broad spectrum of pseudotyped and native mammarenaviruses in cell culture and Tacaribe virus infection in mice. In the present study, we evaluated ARN-75039 against pathogenic JUNV in the rigorous guinea pig infection model. The compound was well-tolerated and had favorable pharmacokinetics supporting once-per-day oral dosing in guinea pigs. Importantly, significant protection against JUNV challenge was observed even when ARN-75039 was withheld until 6 days after the viral challenge when clinical signs of disease are starting to develop. We also show that ARN-75039 combination treatment with favipiravir, a viral polymerase inhibitor, results in synergistic activity in vitro and improves survival outcomes in JUNV-challenged guinea pigs. Our findings support the continued development of ARN-75039 as an attractive therapeutic candidate for treating mammarenaviral hemorrhagic fevers, including those associated with NWM infection.
登录
查看更多内容
影响因子：
3.8
作者：
Mendenhall M;Russell A;Smee DF;Hall JO;Skirpstunas R;Furuta Y;Gowen BB
通讯作者：
Gowen BB
影响因子：
7.6
作者：
Furuta, Yousuke;Gowen, Brian B.;Takahashi, Kazumi;Shiraki, Kimiyasu;Smee, Donald F.;Barnard, Dale L.
通讯作者：
Barnard, Dale L.
影响因子：
12
作者：
Pablo Escalera-Antezana, Juan;Rodriguez-Villena, Omar J.;Rodriguez-Morales, Alfonso J.
通讯作者：
Rodriguez-Morales, Alfonso J.
影响因子：
--
作者：
Grande-Pérez A;Martin V;Moreno H;de la Torre JC
通讯作者：
de la Torre JC
影响因子：
4.9
作者：
Mendenhall, Michelle;Russell, Andrew;Gowen, Brian B.
通讯作者：
Gowen, Brian B.