Design and In Vitro Evaluation of Novel GC373-like SARS-CoV-2 Main Protease Inhibitors

TL;DR

Researchers designed new SARS-CoV-2 protease inhibitors based on the GC373 scaffold to improve solubility and effectiveness against the virus.

Contribution

Novel GC373-like inhibitors with modified glutamine-mimic residues were designed and tested for improved antiviral properties.

Findings

The new inhibitors showed micromolar activity against SARS-CoV-2 Mpro in enzymatic assays.

Molecular docking and MM-PBSA analyses confirmed stable binding of the inhibitors to the protease active site.

The compounds offer a foundation for optimizing electrophilic warheads and residue interactions in future drug development.

Abstract

Significant advances in coronavirus immunoprophylaxis have enabled the control of the SARS-CoV-2 pandemic. However, the continued emergence of SARS-CoV-2 variants with immune escape potential highlights the need for effective direct-acting antivirals targeting conserved viral enzymes. The SARS-CoV-2 main protease (Mpro) remains one of the most promising antiviral drug targets due to its essential role in viral replication and the high conservation of its active site across coronavirus variants. Building upon the established GC373 scaffold, we designed, synthesized, and biochemically evaluated two novel GC373-like peptidomimetic inhibitors incorporated modified glutamine-mimic residues. These analogs were designed to enhance solubility and metabolic resilience while retaining key recognition features within the Mpro active site. Both compounds demonstrated micromolar inhibitory activity in enzymatic assays, supported by molecular docking and MM-PBSA analyses consistent with stable binding. The proposed inhibitors represent viable scaffolds for further optimization of electrophilic warheads and S1/S2 residue interactions. These findings contribute to the rational design of next-generation Mpro inhibitors and align with ongoing efforts to expand the chemical space of SARS-CoV-2 antiviral agents.

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