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Structural basis of main proteases of MERS-CoV bound to antineoplastic drug carmofur
Li Guo1, Pei Zeng2, Xuelan Zhou2
1Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen, China.
Abstract:
Recurrent epidemics of coronaviruses have posed significant threats to human life and health. The mortality rate of patients infected with the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is 35 %. The main protease (Mpro) plays a crucial role in the MERS-CoV life cycle, and Mpro exhibited a high degree of conservation among different coronaviruses. Therefore inhibition of Mpro has become an effective strategy for the development of broad-spectrum anti-coronaviral drugs. The inhibition of SARS-CoV-2 Mpro by the anti-tumor drug carmofur has been revealed, but structural studies of carmofur in complex with Mpro from other types of coronavirus have not been reported. Hence, we revealed the structure of the MERS-CoV Mpro-carmofur complex, analysed the structural basis for the binding of carmofur to MERS-CoV Mpro in detail, and compared the binding patterns of carmofur to Mpros of two different coronaviruses, MERS-CoV and SARS-CoV-2. Considering the importance of Mpros for coronavirus therapy, structural understanding of Mpro inhibition by carmofur could contribute to the design and development of novel antiviral drugs with safe and broad-spectrum efficacy.
Insights
The study reveals the structure of MERS-CoV Mpro bound to carmofur, detailing how this anti-tumor drug inhibits the virus. This structural insight aids in designing broad-spectrum antiviral drugs against coronaviruses.
Area of Science:
- Structural Biology
- Virology
- Drug Discovery
Background:
- Coronaviruses, including MERS-CoV, cause severe disease with high mortality rates.
- The main protease (Mpro) is essential for coronavirus replication and a conserved target for antiviral therapies.
- Carmofur, an anti-tumor drug, has shown inhibitory effects against SARS-CoV-2 Mpro.
Purpose of the Study:
- To determine the structure of the MERS-CoV Mpro-carmofur complex.
- To analyze the structural basis of carmofur binding to MERS-CoV Mpro.
- To compare carmofur's binding to Mpro from MERS-CoV and SARS-CoV-2.
Main Methods:
- X-ray crystallography to determine the complex structure.
- Structural analysis and comparison of Mpro-carmofur interactions.
- Bioinformatics tools for comparative analysis.
Main Results:
- The crystal structure of the MERS-CoV Mpro-carmofur complex was elucidated.
- Detailed analysis revealed specific interactions between carmofur and MERS-CoV Mpro.
- Comparison highlighted similarities and differences in carmofur binding to Mpro from MERS-CoV and SARS-CoV-2.
Conclusions:
- Structural understanding of carmofur inhibition of MERS-CoV Mpro provides a basis for developing novel antiviral drugs.
- Carmofur's conserved binding mechanism across different coronavirus Mpro targets suggests potential for broad-spectrum efficacy.
- This research contributes to the rational design of new therapeutics against emerging coronavirus threats.
