Complete Protection from SARS-CoV-2 Lung Infection in Mice Through Combined Intranasal Delivery of PIKfyve Kinase and TMPRSS2 Protease Inhibitors.
Complete Protection from SARS-CoV-2 Lung Infection in Mice Through Combined Intranasal Delivery of PIKfyve Kinase and TMPRSS2 Protease Inhibitors.
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通过联合鼻内递送 PIKfyve 激酶和 TMPRSS2 蛋白酶抑制剂，完全保护小鼠免受 SARS-CoV-2 肺部感染。
DOI：
10.1101/2023.07.19.549731
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Balistreri,Giuseppe
中科院分区：
文献类型：
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作者：
Kant,Ravi;Kareinen,Lauri;Ojha,Ravi;Strandin,Tomas;Saber,SaberHassan;Lesnikova,Angelina;Kuivanen,Suvi;Sirnonen,Tarja;Joensuu,Merja;Vapalahti,Olli;Kirchhausen,Tom;Kipar,Anja;Balistreri,Giuseppe
由于病毒基因组突变，SARS-CoV-2 的新出现变异可显着降低疫苗和中和抗体的预防和治疗效果。靶向感染所需的细胞宿主因子提供了克服这一问题的补充策略，因为宿主基因组在感染生命周期内不易受到变异的影响。内体 PIKfyve 磷酸肌醇激酶和丝氨酸蛋白酶 TMPRSS2 的酶活性对于介导两种互补的病毒进入途径的感染至关重要。使用小分子抑制剂阿匹莫德二甲磺酸盐和萘莫司他甲磺酸盐同时抑制培养细胞的酶活性，可协同防止病毒进入和感染天然 SARS-CoV-2 和表达 SARS-CoV-2 表面刺突 (S) 蛋白的水泡性口炎病毒 (VSV)-SARS-CoV-2 嵌合体和相关变体。我们现在报告，通过鼻内联合给药极低剂量的阿匹莫德二甲磺酸盐和甲磺酸萘莫司他，预防性预防鼻内感染 SARS-CoV-2 beta 的小鼠肺部感染，其制剂在室温下可稳定超过 3 个月。感染后 6 小时内服用这些药物并不能抑制肺部感染，但可以显着减少受感染气道上皮细胞的死亡。该药物组合配方的高效性和简单性表明其适合在家庭、护理设施以及不易获得冷藏的条件下作为针对 SARS-CoV-2 感染的预防或治疗性治疗。
Emerging variants of concern of SARS-CoV-2 can significantly reduce the prophylactic and therapeutic efficacy of vaccines and neutralizing antibodies due to mutations in the viral genome. Targeting cell host factors required for infection provides a complementary strategy to overcome this problem since the host genome is less susceptible to variation during the life span of infection. The enzymatic activities of the endosomal PIKfyve phosphoinositide kinase and the serine protease TMPRSS2 are essential to meditate infection in two complementary viral entry pathways. Simultaneous inhibition in cultured cells of their enzymatic activities with the small molecule inhibitors apilimod dimesylate and nafamostat mesylate synergistically prevent viral entry and infection of native SARS-CoV-2 and vesicular stomatitis virus (VSV)-SARS-CoV-2 chimeras expressing the SARS-CoV-2 surface spike (S) protein and of variants of concern. We now report prophylactic prevention of lung infection in mice intranasally infected with SARS-CoV-2 beta by combined intranasal delivery of very low doses of apilimod dimesylate and nafamostat mesylate, in a formulation that is stable for over 3 months at room temperature. Administration of these drugs up to 6 hours post infection did not inhibit infection of the lungs but substantially reduced death of infected airway epithelial cells. The efficiency and simplicity of formulation of the drug combination suggests its suitability as prophylactic or therapeutic treatment against SARS-CoV-2 infection in households, point of care facilities, and under conditions where refrigeration would not be readily available.