Liu Jia, Wang Furun, Wang Xi, Fan Shiyong, Li Yufeng, Xu Mingyue, Hu Hengrui, Liu Ke, Zheng Bohong, Wang Lingchao, Zhang Huanyu, Li Jiang, Li Wei, Zhang Wenpeng, Hu Zhihong, Cao Ruiyuan, Zhuang Xiaomei, Wang Manli, Zhong Wu
State Key Laboratory of Virology Wuhan Institute of Virology Center for Biosafety Mega-Science Chinese Academy of Sciences Wuhan China.
National Engineering Research Center for the Emergency Drug Beijing Institute of Pharmacology and Toxicology Beijing China.
MedComm (2020). 2023 Jan 19;4(1):e206. doi: 10.1002/mco2.206. eCollection 2023 Feb.
Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC) in human lungs. This study provides insights into the route-dependent pulmonary biodistribution of TET associated with its efficacy.
在中国,粉防己碱(TET)已被用于治疗矽肺病数十年。本研究的目的是促进TET对严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染的合理重新利用。在本研究中,我们证实TET在非洲绿猴肾(Vero E6)、人肝癌(Huh7)和人肺腺癌上皮(Calu-3)细胞系中对SARS-CoV-2具有抗病毒效力。TET在SARS-CoV-2的早期进入阶段发挥作用,并阻碍病毒从早期内体向溶酶体的细胞内运输。一项使用腺病毒(AdV)5-人血管紧张素转换酶2(hACE2)转导小鼠的体内研究表明,并不能降低肺部病毒载量,但它能显著减轻SARS-CoV-2感染小鼠肺部的病理损伤。基于体内和体外模型研究了TET的全身临床前药代动力学,并探索了TET的途径依赖性生物分布。TET具有较大的分布容积,这导致其在组织中的高蓄积。吸入给药有助于TET靶向肺部并减少其在其他组织中的暴露,从而减轻其脱靶毒性。根据现有的人体药代动力学数据,在人肺中达到未结合TET的90%最大有效浓度(EC)似乎是可行的。本研究为TET与其疗效相关的途径依赖性肺部生物分布提供了见解。