Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies.
Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies.
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DOI：
10.1016/j.antiviral.2022.105367
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发表时间：
2022-08
影响因子：
7.6
通讯作者：
中科院分区：
文献类型：
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作者：
由严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引发的2019年冠状病毒病(新冠肺炎)大流行继续对全球健康构成严重威胁。我们先前报道，AAK1、BIKE和GAK是数字相关激酶家族的成员，在病毒进入和组装/输出过程中控制着多个RNA病毒的细胞内运输。在这里，我们使用遗传学和药理学的方法，探索NAKS与SARS-CoV-2感染的功能相关性。SiRNA介导的AAK1、BIKE、GAK和NAK家族第四成员STK16的缺失抑制了人肺上皮细胞中SARS-CoV-2的感染。具有AAK1/BIKE、GAK或STK16活性的已知和新型小分子均可抑制SARS-CoV-2感染。此外，已批准的抗癌药物舒尼替尼和厄洛替尼分别具有较强的抗AAK1/BIKE和GAK活性，联合治疗在体外显示了抗SARS-CoV-2感染的协同效应。添加时间实验表明，AAK1和BIKE的药理抑制抑制了病毒的进入以及SARS-CoV-2生命周期的后期。最后，siRNAs抑制NAKS的表达，抑制了野生型和SARS-CoV-2假病毒的入侵。这些发现为深入了解NAKS在SARS-CoV-2感染中的作用提供了洞察力，并建立了一个原则证明，即对NAKS的药理抑制可能被用作治疗SARS-CoV-2的宿主靶向方法，对其他冠状病毒具有潜在的影响。
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose serious threats to global health. We previously reported that AAK1, BIKE and GAK, members of the Numb-associated kinase family, control intracellular trafficking of multiple RNA viruses during viral entry and assembly/egress. Here, using both genetic and pharmacological approaches, we probe the functional relevance of NAKs for SARS-CoV-2 infection. siRNA-mediated depletion of AAK1, BIKE, GAK, and STK16, the fourth member of the NAK family, suppressed SARS-CoV-2 infection in human lung epithelial cells. Both known and novel small molecules with potent AAK1/BIKE, GAK or STK16 activity suppressed SARS-CoV-2 infection. Moreover, combination treatment with the approved anti-cancer drugs, sunitinib and erlotinib, with potent anti-AAK1/BIKE and GAK activity, respectively, demonstrated synergistic effect against SARS-CoV-2 infection in vitro. Time-of-addition experiments revealed that pharmacological inhibition of AAK1 and BIKE suppressed viral entry as well as late stages of the SARS-CoV-2 life cycle. Lastly, suppression of NAKs expression by siRNAs inhibited entry of both wild type and SARS-CoV-2 pseudovirus. These findings provide insight into the roles of NAKs in SARS-CoV-2 infection and establish a proof-of-principle that pharmacological inhibition of NAKs can be potentially used as a host-targeted approach to treat SARS-CoV-2 with potential implications to other coronaviruses.
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影响因子：
3.4
作者：
Asquith CRM;Laitinen T;Bennett JM;Godoi PH;East MP;Tizzard GJ;Graves LM;Johnson GL;Dornsife RE;Wells CI;Elkins JM;Willson TM;Zuercher WJ
通讯作者：
Zuercher WJ
DOI：
10.1186/s12941-021-00438-7
发表时间：
2021-05-18
影响因子：
5.7
作者：
Mallah SI;Ghorab OK;Al-Salmi S;Abdellatif OS;Tharmaratnam T;Iskandar MA;Sefen JAN;Sidhu P;Atallah B;El-Lababidi R;Al-Qahtani M
通讯作者：
Al-Qahtani M
DOI：
10.1016/s2213-2600(21)00331-3
发表时间：
2021-12
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Marconi VC;Ramanan AV;de Bono S;Kartman CE;Krishnan V;Liao R;Piruzeli MLB;Goldman JD;Alatorre-Alexander J;de Cassia Pellegrini R;Estrada V;Som M;Cardoso A;Chakladar S;Crowe B;Reis P;Zhang X;Adams DH;Ely EW;COV-BARRIER Study Group
通讯作者：
COV-BARRIER Study Group
影响因子：
--
作者：
Chiem, Kevin;Ye, Chengjin;Martinez-Sobrido, Luis
通讯作者：
Martinez-Sobrido, Luis
影响因子：
3.4
作者：
Asquith, Christopher R. M.;Laitinen, Tuomo;Poso, Antti
通讯作者：
Poso, Antti