Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Area of Science:

• Virology
• Drug Discovery
• Structural Biology

Background:

• Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic.
• Approved vaccines and antivirals like remdesivir, molnupiravir, and nirmatrelvir/ritonavir are vital but insufficient against new variants.
• The SARS-CoV-2 papain-like protease (PL^pro) is a key viral target due to its role in polyprotein processing and immune modulation.

Purpose of the Study:

• To review advancements in structure-based design and high-throughput screening of SARS-CoV-2 PL^pro inhibitors.
• To discuss the potential of PL^pro as a target for novel antiviral therapies.
• To identify knowledge gaps for advancing PL^pro inhibitors into clinical use.

Main Methods:

• Structure-based drug design approaches.
• High-throughput screening (HTS) assays.
• Analysis of published research on SARS-CoV-2 PL^pro inhibitors.

Main Results:

• Significant progress in developing non-covalent PL^pro inhibitors with improved pharmacokinetic profiles.
• Development of first-in-class covalent inhibitors targeting PL^pro.
• Identification of promising drug candidates for further investigation.

Conclusions:

• SARS-CoV-2 PL^pro remains a highly promising target for novel antiviral drug development.
• Continued research is needed to address remaining challenges and translate PL^pro inhibitors to clinical application.
• Novel inhibitors are essential to combat the threat of SARS-CoV-2 variants.