In Vivo protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice.
In Vivo protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice.
复制标题
ATN-161 在 k18-hACE2 转基因小鼠体内防止 SARS-CoV-2 感染。
DOI：
10.1016/j.lfs.2021.119881
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发表时间：
2021-11-01
期刊：
影响因子：
6.1
通讯作者：
Bix G
中科院分区：
文献类型：
--
作者：
Amruta N;Engler-Chiurazzi EB;Murray-Brown IC;Gressett TE;Biose IJ;Chastain WH;Befeler JB;Bix G
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）是一种在世界范围内传播的传染病。目前的治疗方法在可得性和疗效方面都是有限的，因此迫切需要提高我们对促进感染的因素的理解，以便更有效地治疗受感染的个体并遏制这种大流行。我们和其他人之前已经在体外证明了SARS-CoV-2刺突蛋白、整合素α5β1和人ACE2之间的相互作用对促进病毒进入宿主细胞的重要性。我们之前发现，临床验证的小肽ATN-161对整合素α5β1的抑制抑制了这些刺突蛋白的相互作用和体外细胞感染。在我们之前的研究结果的基础上，本研究进一步评估了ATN-161对k18-hACE2转基因（SARS-CoV-2易感）小鼠体内SARS-CoV-2感染的治疗潜力。我们发现，在鼻内接种SARS-CoV-2后48小时内单次或多次静脉注射ATN-161 （1 mg/kg）可导致大多数小鼠在感染72小时后肺部病毒载量、病毒免疫荧光和肺组织学改善。此外，ATN-161降低了SARS-CoV-2诱导的肺整合素α5和αv （α5相关的整合素，也与SARS-CoV-2相互作用有关）以及C-X-C基序趋化因子配体10 （Cxcl10）的表达增加，进一步支持了这些整合素的潜在参与以及ATN-161在SARS-CoV-2感染中的抗炎潜力。据我们所知，这是第一个证明靶向整合素α5β1在体内治疗SARS-CoV-2感染的潜在疗效的研究，并支持ATN-161作为一种新型SARS-CoV-2治疗药物的开发。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin α5β1, and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin α5β1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 h after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence, and improved lung histology in a majority of mice 72 h post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin α5 and αv (an α5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C–X–C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin α5β1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.
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影响因子：
5.8
作者：
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通讯作者：
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影响因子：
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作者：
Clarke NE;Fisher MJ;Porter KE;Lambert DW;Turner AJ
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DOI：
10.1101/2020.06.15.153387
发表时间：
2021-01-01
期刊：
JACC. Basic to translational science
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DOI：
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发表时间：
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影响因子：
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影响因子：
158.5
作者：
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