Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.
Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.
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用于COVID 19潜在治疗的静脉内冠状病毒3CL蛋白酶抑制剂的临床前表征。
DOI：
10.1038/s41467-021-26239-2
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发表时间：
2021-10-18
影响因子：
16.6
通讯作者：
Allerton C
中科院分区：
文献类型：
--
作者：
Boras B;Jones RM;Anson BJ;Arenson D;Aschenbrenner L;Bakowski MA;Beutler N;Binder J;Chen E;Eng H;Hammond H;Hammond J;Haupt RE;Hoffman R;Kadar EP;Kania R;Kimoto E;Kirkpatrick MG;Lanyon L;Lendy EK;Lillis JR;Logue J;Luthra SA;Ma C;Mason SW;McGrath ME;Noell S;Obach RS;O' Brien MN;O'Connor R;Ogilvie K;Owen D;Pettersson M;Reese MR;Rogers TF;Rosales R;Rossulek MI;Sathish JG;Shirai N;Steppan C;Ticehurst M;Updyke LW;Weston S;Zhu Y;White KM;García-Sastre A;Wang J;Chatterjee AK;Mesecar AD;Frieman MB;Anderson AS;Allerton C
由SARS-CoV-2病毒引起的COVID-19已成为全球大流行病。3CL蛋白酶是一种病毒编码的蛋白质，在广谱冠状病毒中是必需的，没有接近的人类类似物。PF-00835231是一种3CL蛋白酶抑制剂，作为单一药物对SARS-CoV-2表现出有效的体外抗病毒活性。在本文中，我们报告了磷酸盐前药PF-07304814的设计和表征，以使PF-00835231能够在人体中递送和预计持续全身暴露，从而抑制冠状病毒家族3CL蛋白酶活性，并对人类宿主蛋白酶靶标具有选择性。此外，我们表明PF-00835231与瑞德西韦联合使用具有相加/协同活性。我们提供了ADME、安全性、体外和体内抗病毒活性数据，支持PF-07304814作为潜在COVID-19治疗药物的临床评价。PF-00835231在体外对SARS-CoV-2的3CL蛋白酶有抑制作用。在这里，作者表明前药PF-07304814具有广谱活性，可抑制小鼠中的SARS-CoV和SARS-CoV-2，其ADME和安全性特征支持临床开发。
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment. The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.
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影响因子：
6.4
作者：
Agnihothram S;Yount BL Jr;Donaldson EF;Huynh J;Menachery VD;Gralinski LE;Graham RL;Becker MM;Tomar S;Scobey TD;Osswald HL;Whitmore A;Gopal R;Ghosh AK;Mesecar A;Zambon M;Heise M;Denison MR;Baric RS
通讯作者：
Baric RS
影响因子：
5
作者：
Grum-Tokars, Valerie;Ratia, Kiira;Begaye, Adrian;Baker, Susan C.;Mesecar, Andrew D.
通讯作者：
Mesecar, Andrew D.
影响因子：
8.8
作者：
Garcia G Jr;Sharma A;Ramaiah A;Sen C;Purkayastha A;Kohn DB;Parcells MS;Beck S;Kim H;Bakowski MA;Kirkpatrick MG;Riva L;Wolff KC;Han B;Yuen C;Ulmert D;Purbey PK;Scumpia P;Beutler N;Rogers TF;Chatterjee AK;Gabriel G;Bartenschlager R;Gomperts B;Svendsen CN;Betz UAK;Damoiseaux RD;Arumugaswami V
通讯作者：
Arumugaswami V
影响因子：
3.8
作者：
Hegyi, A;Ziebuhr, J
通讯作者：
Ziebuhr, J
影响因子：
5.4
作者：
Deng, Xufang;Sarah, E. St. John;Baker, Susan C.
通讯作者：
Baker, Susan C.