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Design and In Vitro Evaluation of Novel GC373-like SARS-CoV-2 Main Protease Inhibitors
Aleksandra A Kuznetsova1, Aleksandr P Makhin2, Anatoliy A Bulygin1
1Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Current Issues in Molecular Biology
|February 27, 2026
Summary
New peptidomimetic inhibitors targeting the SARS-CoV-2 main protease (Mpro) show promise for antiviral development. These compounds demonstrate micromolar activity, offering potential for future COVID-19 treatments against emerging variants.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- Coronavirus immunoprophylaxis has advanced, but emerging SARS-CoV-2 variants necessitate direct-acting antivirals.
- The SARS-CoV-2 main protease (Mpro) is a conserved, essential target for antiviral drug development.
Purpose of the Study:
- To design, synthesize, and evaluate novel Mpro inhibitors based on the GC373 scaffold.
- To enhance inhibitor solubility and metabolic stability while maintaining Mpro active site recognition.
Main Methods:
- Peptidomimetic inhibitor design and synthesis.
- Biochemical evaluation using enzymatic assays.
- Molecular docking and MM-PBSA computational analyses.
Main Results:
- Two novel GC373-like inhibitors were synthesized and evaluated.
- Both compounds exhibited micromolar inhibitory activity against Mpro.
- Computational analyses confirmed stable binding interactions within the Mpro active site.
Conclusions:
- The developed inhibitors serve as viable scaffolds for next-generation Mpro-targeted antivirals.
- Findings support the rational design of novel SARS-CoV-2 antiviral agents.
- These compounds contribute to expanding the chemical space for COVID-19 therapeutics.
