p97 Inhibitors Possessing Antiviral Activity Against SARS-CoV-2 and Low Cytotoxicity.

Area of Science:

• Biochemistry
• Virology
• Medicinal Chemistry

Background:

• p97 (valosin-containing protein, VCP) is an AAA+ ATPase crucial for protein quality control.
• p97 is implicated in cellular homeostasis and has been explored as an anticancer target.
• Emerging evidence highlights p97 as a pro-viral host factor, making its inhibitors potential antiviral agents.

Purpose of the Study:

• To design and synthesize novel p97 inhibitors.
• To evaluate these inhibitors for anti-p97 activity, cytotoxicity, and antiviral efficacy against SARS-CoV-2.
• To investigate the binding modes of selected inhibitors using molecular docking.

Main Methods:

• Novel p97 inhibitors were synthesized by rearranging the central fused ring of existing compounds.
• In vitro assays were used to assess p97 inhibition, cytotoxicity, and antiviral activity against SARS-CoV-2.
• Molecular docking simulations were performed to analyze inhibitor-protein interactions.

Main Results:

• Two novel compounds demonstrated enhanced inhibition of p97 compared to parent molecules.
• These compounds exhibited significant antiviral activity against SARS-CoV-2 without notable cytotoxicity.
• Molecular docking confirmed that the binding mode remained largely consistent with parent compounds.

Conclusions:

• Structurally novel p97 inhibitors with low toxicity have been developed.
• These inhibitors show promising antiviral potential against SARS-CoV-2 and possibly other viruses.
• Further research and analog development are warranted to explore p97 as a host antiviral target.