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What coronavirus 3C-like protease tells us: From structure, substrate selectivity, to inhibitor design
Muya Xiong1,2, Haixia Su1,2, Wenfeng Zhao1
1CAS Key Laboratory of Receptor Research|Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Abstract:
The emergence of a variety of coronaviruses (CoVs) in the last decades has posed huge threats to human health. Especially, the ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 70 million infections and over 1.6 million of deaths worldwide in the past few months. None of the efficacious antiviral agents against human CoVs have been approved yet. 3C-like protease (3CLpro ) is an attractive target for antiviral intervention due to its essential role in processing polyproteins translated from viral RNA, and its conserved structural feature and substrate specificity among CoVs in spite of the sequence variation. This review focuses on all available crystal structures of 12 CoV 3CLpro s and their inhibitors, and intends to provide a comprehensive understanding of this protease from multiple aspects including its structural features, substrate specificity, inhibitor binding modes, and more importantly, to recapitulate the similarity and diversity among different CoV 3CLpro s and the structure-activity relationship of various types of inhibitors. Such an attempt could gain a deep insight into the inhibition mechanisms and drive future structure-based drug discovery targeting 3CLpro s.
Insights
This review analyzes 12 coronavirus 3C-like proteases (3CLpro) and their inhibitors, highlighting structural similarities and differences. Understanding these viral proteases is crucial for developing new antiviral drugs against coronaviruses.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Coronaviruses (CoVs) pose significant global health threats, exemplified by the COVID-19 pandemic.
- No effective antiviral treatments are currently approved for human CoVs.
- 3C-like protease (3CLpro) is a conserved and essential enzyme in CoVs, making it a prime target for antiviral drug development.
Purpose of the Study:
- To comprehensively review available crystal structures of 12 CoV 3CLpro enzymes.
- To analyze the structural features, substrate specificities, and inhibitor binding modes of these proteases.
- To elucidate similarities and diversities among different CoV 3CLpro structures and guide structure-based drug discovery.
Main Methods:
- Systematic review of published crystal structures of 12 CoV 3CLpro enzymes.
- Analysis of structural data to understand enzyme-inhibitor interactions.
- Comparative analysis of structural features and substrate specificities across different CoVs.
Main Results:
- Detailed structural insights into 12 CoV 3CLpro enzymes.
- Characterization of conserved and variable regions within the 3CLpro active site.
- Identification of diverse inhibitor binding modes and their structure-activity relationships.
Conclusions:
- The structural conservation of 3CLpro across CoVs supports its potential as a broad-spectrum antiviral target.
- Understanding the structural nuances and inhibitor interactions is key to designing effective antiviral agents.
- This review provides a foundation for future structure-based drug discovery efforts against 3CLpro.
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