Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro...

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• The COVID-19 pandemic necessitates novel antiviral treatments against SARS-CoV-2.
• The SARS-CoV-2 papain-like protease (PLpro) is a validated drug target crucial for viral replication.
• Drug repurposing offers a rapid strategy for identifying potential antiviral therapies.

Purpose of the Study:

• To identify novel inhibitors of SARS-CoV-2 PLpro through high-throughput screening.
• To optimize existing PLpro inhibitors based on the piperidine scaffold for improved efficacy and drug-like properties.
• To evaluate the antiviral activity of optimized inhibitors against SARS-CoV-2 in vitro.

Main Methods:

• Screening of the ReFRAME library (11,804 compounds) for PLpro inhibitors.
• Medicinal chemistry optimization of piperidine-scaffold inhibitors (5c, 3k).
• In vitro ADME studies, co-crystallization, and antiviral assays in a SARS-CoV-2 infection model.

Main Results:

• No compounds from the ReFRAME library showed significant PLpro inhibition.
• Optimization efforts led to compounds with improved solubility and stability.
• Co-crystallization provided structural insights for inhibitor design.
• Optimized inhibitors demonstrated modest antiviral activity in vitro.

Conclusions:

• Initial broad screening failed to identify viable PLpro inhibitors.
• Piperidine-scaffold inhibitors were successfully modified to enhance ADME properties.
• Further optimization is required, but developed compounds show promise as SARS-CoV-2 antivirals.