Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation

Author(s):Show less -

Sousa, Bruna K. P. ; Mottin, Melina ; Seanego, Donald ; Jurisch, Christopher D. ; Rodrigues, Beatriz S. A. ; da Silva, Veronica L. S. ; Andrade, Milene Aparecida ; Morais Jr, Gilberto S. ; Boerin, Diogo F. ; Froes, Thamires Q. ; Motta, Flavia Nader ; Nonato, M. Cristina ; Bastos, Izabela D. M. ; Chibale, Kelly ; Gessner, Richard K. ; Andrade, Carolina Horta

• Document type: Journal article
• Source: ACS Medicinal Chemistry Letters; v. N/A, p. 10-pg., 2024-12-02.

Abstract

The SARS-CoV-2 pandemic has significantly challenged global public health, highlighting the need for effective therapeutic options. This study focuses on the papain-like protease (PLpro) of SARS-CoV-2, which is a critical enzyme for viral polyprotein processing, maturation, and immune evasion. We employed a combined approach that began with computational models in a virtual screening campaign, prioritizing compounds from our in-house chemical library against PLpro. Out of 81 virtual hits evaluated through enzymatic and biophysical assays, we identified a modest inhibitor featuring a naphthyridine core with an IC50 of 73.61 mu M and a K i of 22 mu M. Expanding our exploration, we synthesized and assessed 30 naphthyridine analogues, three of which emerged as promising noncovalent, nonpeptidomimetic inhibitors with IC50 values between 15.06 and 51.81 mu M. Furthermore, in vitro ADMET assays revealed these compounds to possess moderate aqueous solubility, low cytotoxicity, and high microsomal stability, making them excellent candidates for further development targeting SARS-CoV-2 PLpro. (AU)

• FAPESP's process: 21/13237-5 - Search for Human Dihydroorotate Dehydrogenase inhibitors as a new strategy against COVID-19 disease
• Grantee: Aline Dias da Purificação
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 20/06190-0 - Drug repurposing and search of selective inhibitors for human dihydroorotate dehydrogenase as a strategy in fighting against COVID-19
• Grantee: Maria Cristina Nonato
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/15854-4 - Search and characterization of inhibitors of the enzyme papain-like protease (PL-Pro) of SarS-Cov-2
• Grantee: Diogo Fernandes Boerin
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/05369-6 - Artificial inteligence driven drug repositioning strategy for COVID-19
• Grantee: Fabio Trindade Maranhão Costa
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/10084-3 - Development of covalent inhibitors of the enzyme dihydroorotate dehydrogenase for the discovery of therapeutic candidates for Chagas disease
• Grantee: Bruna Fleck Godoi
• Support Opportunities: Scholarships in Brazil - Master