毛皮
TMPRS2型
病毒进入
病毒
蛋白酵素
体内
体外
化学
受体
药理学
酶
生物
分子生物学
生物化学
病毒学
病毒复制
医学
2019年冠状病毒病(COVID-19)
生物技术
疾病
病理
传染病(医学专业)
作者
Srinivasa Rao Palla,Chenwei Li,Tai‐Ling Chao,Hoi-Ling Vienn Lo,Jia-Jin Liu,Max Yu-Chen Pan,Yu‐Ting Chiu,Wen‐Chin Lin,Chih‐Wei Hu,Chuen-Mi Yang,Yi‐Ying Chen,Jun‐Tung Fang,Sheng‐Wei Lin,Yi-Tzu Lin,Hsiao‐Ching Lin,Chih‐Jung Kuo,Lily Wang,Sui‐Yuan Chang,Po‐Huang Liang
标识
DOI:10.1016/j.antiviral.2023.105735
摘要
A class of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones were designed and synthesized via Michael addition, cyclization, aldol condensation, and deprotonation to inhibit the human transmembrane protease serine 2 (TMPRSS2) and Furin, which are involved in priming the SARS-CoV-2 Spike for virus entry. The most potent inhibitor 2f (81) was found to efficiently inhibit the replication of various SARS-CoV-2 delta and omicron variants in VeroE6 and Calu-3 cells, with EC50 range of 0.001-0.026 μM by pre-incubation with the virus to avoid the virus entry. The more potent antiviral activities than the proteases inhibitory activities led to discovery that the synthesized compounds also inhibited Spike's receptor binding domain (RBD):angiotensin converting enzyme 2 (ACE2) interaction as a main target, and their antiviral activities were enhanced by inhibiting TMPRSS2 and/or Furin. To further confirm the blocking effect of 2f (81) on virus entry, SARS-CoV-2 Spike pseudovirus was used in the entry assay and the results showed that the compound inhibited the pseudovirus entry in a ACE2-dependent pathway, via mainly inhibiting RBD:ACE2 interaction and TMPRSS2 activity in Calu-3 cells. Finally, in the in vivo animal model of SARS-CoV-2 infection, the oral administration of 25 mg/kg 2f (81) in hamsters resulted in reduced bodyweight loss and 5-fold lower viral RNA levels in nasal turbinate three days post-infection. Our findings demonstrated the potential of the lead compound for further preclinical investigation as a potential treatment for SARS-CoV-2.
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