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Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental
Bruna K P Sousa1,2, Melina Mottin1,2,3, Donald Seanego4
1Center for the Research and Advancement in Fragments and Molecular Targets (CRAFT), Faculdade de Ciências Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 05508-070, Brazil.
ACS Medicinal Chemistry Letters
|December 18, 2024
Summary
Researchers identified novel naphthyridine compounds as potential therapeutics against SARS-CoV-2 papain-like protease (PLpro). These inhibitors show promise for further development in combating the COVID-19 pandemic.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- The SARS-CoV-2 pandemic necessitates novel therapeutic strategies.
- The SARS-CoV-2 papain-like protease (PLpro) is essential for viral replication and immune evasion.
Purpose of the Study:
- To identify and develop small molecule inhibitors targeting SARS-CoV-2 PLpro.
- To explore the potential of naphthyridine derivatives as antiviral agents.
Main Methods:
- Virtual screening of an in-house chemical library against SARS-CoV-2 PLpro.
- Enzymatic and biophysical assays to evaluate inhibitor activity.
- Synthesis and assessment of naphthyridine analogues and their ADMET properties.
Main Results:
- A modest naphthyridine-based inhibitor was initially identified.
- Three novel noncovalent, nonpeptidomimetic naphthyridine inhibitors demonstrated significant potency (IC50 values 15.06–51.81 μM).
- These compounds exhibited favorable in vitro ADMET profiles, including moderate solubility, low cytotoxicity, and high microsomal stability.
Conclusions:
- Naphthyridine derivatives represent promising candidates for the development of SARS-CoV-2 PLpro inhibitors.
- The identified compounds warrant further investigation as potential antiviral therapeutics against COVID-19.
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