2. Academic Validation
  3. Synthesis, evaluation, and mechanism of 1-(4-(arylethylenylcarbonyl)phenyl)-4-carboxy-2-pyrrolidinones as potent reversible SARS-CoV-2 entry inhibitors

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.
Srinivasa Rao Palla 1,  Chen-Wei Li 2,  Tai-Ling Chao 3,  Hoi-Ling Vienn Lo 2,  Jia-Jin Liu 2,  Max Yu-Chen Pan 4,  Yu-Ting Chiu 4,  Wen-Chin Lin 5,  Chih-Wei Hu 6,  Chuen-Mi Yang 7,  Yi-Ying Chen 8,  Jun-Tung Fang 3,  Sheng-Wei Lin 9,  Yi-Tzu Lin 9,  Hsiao-Ching Lin 10,  Chih-Jung Kuo 11,  Lily Hui-Ching Wang 12,  Sui-Yuan Chang 13,  Po-Huang Liang 14
Affiliations

Affiliations

  • 1 Institute of Biochemical Sciences, National Taiwan University, 10617, Taiwan; Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan.
  • 2 Institute of Biochemical Sciences, National Taiwan University, 10617, Taiwan.
  • 3 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan.
  • 4 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan.
  • 5 Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 23742, Taiwan; Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 11490, Taiwan.
  • 6 Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 23742, Taiwan; Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 11490, Taiwan; Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan.
  • 7 Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 23742, Taiwan.
  • 8 Institute of Preventive Medicine, National Defense Medical Center, New Taipei City 23742, Taiwan; Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan.
  • 9 Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan.
  • 10 Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan; Institute of Biochemical Sciences, National Taiwan University, 10617, Taiwan; Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan.
  • 11 Department of Veterinary Medicine, College of Veterinary Medicine, National Chung Hsing University, Taichung 40227, Taiwan. Electronic address: ck476@dragon.nchu.edu.tw.
  • 12 Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan; School of Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan. Electronic address: lilywang@life.nthu.edu.tw.
  • 13 Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 10048, Taiwan; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan. Electronic address: sychang@ntu.edu.tw.
  • 14 Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan; Institute of Biochemical Sciences, National Taiwan University, 10617, Taiwan; Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan. Electronic address: phliang@gate.sinica.edu.tw.
PMID: 37858764 DOI: 10.1016/j.antiviral.2023.105735
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.

Keywords

COVID-19; Furin; Pyrrolidinones; RBD:ACE2; SARS-CoV-2; TMPRSS2.

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