Structure-Based Design of Covalent SARS-CoV‑2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166...

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• The COVID-19 pandemic necessitated rapid antiviral development, leading to nirmatrelvir (a main protease inhibitor) as a key treatment.
• Emerging drug resistance, particularly the Mpro E166V mutation, poses a significant threat to current and future COVID-19 therapies.
• This mutation confers cross-resistance to several next-generation Mpro inhibitors.

Purpose of the Study:

• To rationally design and develop novel main protease inhibitors effective against nirmatrelvir-resistant SARS-CoV-2 variants.
• To identify a lead candidate compound that can overcome clinically relevant drug resistance.

Main Methods:

• Rational drug design principles were applied to create inhibitors targeting Mpro.
• In vitro enzymatic assays were used to evaluate inhibitor potency against wild-type and mutant Mpro.
• Structural studies and molecular dynamics simulations were employed to understand inhibitor-protease interactions.
• Antiviral activity was assessed in cell-based assays.

Main Results:

• The lead candidate, Jun13698, demonstrated potent inhibition against both wild-type Mpro and the E166V/A resistant mutants.
• Structural and simulation data confirmed stable complex formation between Jun13698 and both wild-type and mutant proteases.
• Jun13698 exhibited potent enzymatic and antiviral activity, consistent with its structural stability.

Conclusions:

• Jun13698 is a promising next-generation main protease inhibitor.
• This compound effectively overcomes clinically relevant nirmatrelvir resistance mediated by Mpro E166V/A mutations.
• Jun13698 represents a potential therapeutic option for managing drug-resistant COVID-19.