Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.
Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.
复制标题
马赛替尼是一种广泛的冠状病毒3CL抑制剂，可阻断SARS-CoV-2的复制。
DOI：
10.1126/science.abg5827
复制
发表时间：
2021-08-20
期刊：
影响因子：
--
通讯作者：
Tay S
中科院分区：
文献类型：
--
作者：
Drayman N;DeMarco JK;Jones KA;Azizi SA;Froggatt HM;Tan K;Maltseva NI;Chen S;Nicolaescu V;Dvorkin S;Furlong K;Kathayat RS;Firpo MR;Mastrodomenico V;Bruce EA;Schmidt MM;Jedrzejczak R;Muñoz-Alía MÁ;Schuster B;Nair V;Han KY;O'Brien A;Tomatsidou A;Meyer B;Vignuzzi M;Missiakas D;Botten JW;Brooke CB;Lee H;Baker SC;Mounce BC;Heaton NS;Severson WE;Palmer KE;Dickinson BC;Joachimiak A;Randall G;Tay S
在宿主细胞内，严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的RNA基因组被翻译成两个多蛋白，这两个多蛋白被切割成单独的病毒蛋白。被称为MPRO或3CLPro的主要病毒蛋白水解酶在这些裂解过程中起着关键作用，使其成为重要的药物靶点。Drayman等人。从1900种临床安全药物库中确定了8种针对3CLpro的药物。由于与SARS-CoV-2合作的挑战，他们从筛选抑制导致普通感冒的人类冠状病毒复制的药物开始。然后，他们评估了抑制SARS-CoV-2复制和抑制3CLPro的热门药物。马西替尼是一种广谱的抗病毒药物，它能抑制冠状病毒和小核糖核酸病毒的主要蛋白酶，并能有效地减少SARS-CoV-2在小鼠体内的复制。-VV A再用途筛查显示，口服药物Masitinib能够抑制新冠肺炎小鼠模型中的病毒复制。目前迫切需要治疗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染的抗病毒药物。我们筛选了1900种对抗OC43的临床安全药物，OC43是一种导致普通感冒的人类贝塔冠状病毒，并评估了针对SARS-CoV-2的热门药物。20种药物显著抑制了这两种病毒在培养的人类细胞中的复制。这些药物中有8种抑制SARS-CoV-2主要蛋白酶3CLpro的活性，其中最有效的是Masitinib，一种口服生物可用酪氨酸激酶抑制剂。X射线结晶学和生化分析表明，马西替尼是3CLPro的竞争性抑制剂。感染SARS-CoV-2的小鼠在接受Masitinib治疗后，肺部和鼻子中的病毒滴度降低了200倍，肺部炎症也减少了。在体外，Masitinib对所有测试的关注变种也是有效的(B.1.1.7，B.1.351和P.1)。
Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al. identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice. —VV A repurposing screen shows that the orally available drug masitinib is able to inhibit virus replication in mouse-based models of COVID-19. There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).
登录
查看更多内容
冠状病毒主蛋白酶的结构揭示了甲over依蛋白酶折叠与额外的α-螺旋结构域的组合。
影响因子：
11.4
作者：
Anand, Kanchan;Palm, Gottfried J;Mesters, Jeroen R;Siddell, Stuart G;Ziebuhr, John;Hilgenfeld, Rolf
通讯作者：
Hilgenfeld, Rolf
影响因子：
4.8
作者：
Kim, Youngchang;Babnigg, Gyorgy;Jedrzejczak, Robert;Eschenfeldt, William H.;Li, Hui;Maltseva, Natalia;Hatzos-Skintges, Catherine;Gu, Minyi;Makowska-Grzyska, Magdalena;Wu, Ruiying;An, Hao;Chhor, Gekleng;Joachimiak, Andrzej
通讯作者：
Joachimiak, Andrzej
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
Anand, K;Ziebuhr, J;Hilgenfeld, R
通讯作者：
Hilgenfeld, R
影响因子：
5.4
作者：
Froggatt HM;Heaton BE;Heaton NS
通讯作者：
Heaton NS