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<p>SARS-CoV-2 utilizes the cell surface receptor angiotensin-converting enzyme 2 (ACE2) for entry and infection in the host cell. Thus, the molecular interface of the receptor binding domain (RBD) and ACE2 is a potential clinical target for SARS-CoV-2 infection. A small molecule inhibitor of ACE2 could block the entry of SARS-CoV‐2 and its emerging variants. This study characterizes the RBD-ACE2 interaction inhibition activity and antiviral activity of GR 127935. The binding affinity of GR 127935 to ACE2 was confirmed using Surface Plasmon Resonance (SPR). The compound inhibited RBD-ACE2 interaction in the ELISA assay (IC<sub>50</sub> = ~ 17 µM) and effectively blocked the entry of SARS-CoV-2 pseudovirus into HEK293T-ACE2-TMPRSS2 (IC<sub>50</sub> = ~ 1.2 µM). Further, the anti-SARS-CoV-2 activity of GR 127935 was evaluated in vitro using the Vero cell line and a SARS-CoV-2 clinical isolate. The most prominent inhibition (EC<sub>50</sub> = ~ 1.6 µM) was observed when the compound was added during the virus entry step. Finally, the GR 127935 treatment of BALB/c mice infected with the mouse-adapted strain of SARS-CoV-2 resulted in decreased viral load in the lungs along with a lower histopathology score. In summary, the GR 127935 molecule binds to ACE2, inhibits the molecular interaction between RBD and ACE2, and is effective in inhibiting virus replication. Thus, it is a promising potential therapeutic compound for treating human SARS-CoV-2 infections.</p>

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A novel molecule inhibits SARS-CoV-2 RBD binding to the ACE2 receptor, blocks viral entry and exhibits antiviral activity in a murine model

  • 期刊论文

  • 发表日期：

    2026年2月25日

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  • Sanketkumar Nehul,
  • Santhosh Kambaiah Nagaraj,
  • Rohan Narayan,
  • Ankur Singh,
  • Mandar Bhutkar,
  • Vishakha Singh,
  • Ruchi Rani,
  • Harry Kaur,
  • Ashwani Kumar Sharma,
  • Pravindra Kumar,
  • Gaurav Kumar Sharma,
  • Shashank Tripathi,
  • Shailly Tomar

摘要

SARS-CoV-2 utilizes the cell surface receptor angiotensin-converting enzyme 2 (ACE2) for entry and infection in the host cell. Thus, the molecular interface of the receptor binding domain (RBD) and ACE2 is a potential clinical target for SARS-CoV-2 infection. A small molecule inhibitor of ACE2 could block the entry of SARS-CoV‐2 and its emerging variants. This study characterizes the RBD-ACE2 interaction inhibition activity and antiviral activity of GR 127935. The binding affinity of GR 127935 to ACE2 was confirmed using Surface Plasmon Resonance (SPR). The compound inhibited RBD-ACE2 interaction in the ELISA assay (IC50 = ~ 17 µM) and effectively blocked the entry of SARS-CoV-2 pseudovirus into HEK293T-ACE2-TMPRSS2 (IC50 = ~ 1.2 µM). Further, the anti-SARS-CoV-2 activity of GR 127935 was evaluated in vitro using the Vero cell line and a SARS-CoV-2 clinical isolate. The most prominent inhibition (EC50 = ~ 1.6 µM) was observed when the compound was added during the virus entry step. Finally, the GR 127935 treatment of BALB/c mice infected with the mouse-adapted strain of SARS-CoV-2 resulted in decreased viral load in the lungs along with a lower histopathology score. In summary, the GR 127935 molecule binds to ACE2, inhibits the molecular interaction between RBD and ACE2, and is effective in inhibiting virus replication. Thus, it is a promising potential therapeutic compound for treating human SARS-CoV-2 infections.