Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors
Journal
Antiviral research
Journal Volume
219
Date Issued
2023-11
Author(s)
Palla, Srinivasa Rao
Li, Chen-Wei
Lo, Hoi-Ling Vienn
Liu, Jia-Jin
Pan, Max Yu-Chen
Chiu, Yu-Ting
Lin, Wen-Chin
Hu, Chih-Wei
Yang, Chuen-Mi
Chen, Yi-Ying
Fang, Jun-Tung
Lin, Sheng-Wei
Lin, Yi-Tzu
Lin, Hsiao-Ching
Kuo, Chih-Jung
Wang, Lily Hui-Ching
Liang, Po-Huang
Abstract
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.
Subjects
COVID-19; Furin; Pyrrolidinones; RBD:ACE2; SARS-CoV-2; TMPRSS2
SDGs
Type
journal article