Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors
Antiviral Res. 2023 Oct 18;219:105735. doi: 10.1016/j.antiviral.2023.105735. Online ahead of print.ABSTRACTA 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 leve...
Source: Antiviral Research - Category: Virology Authors: Srinivasa Rao Palla Chen-Wei 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 Hui-Ching Wang Sui-Yuan Source Type: research