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Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors
Vathan Kumar1, Kian-Pin Tan2, Ying-Ming Wang1
1Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Abstract:
Severe acute respiratory syndrome (SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CL(pro) of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R(1) or R(4) destabilizes the oxyanion hole in the 3CL(pro). Interestingly, 3f, 3g and 3m could inhibit both NA and 3CL(pro) and serve as a starting point to develop broad-spectrum antiviral agents.
Insights
New antiviral compounds show promise against SARS and MERS. Researchers identified molecules that inhibit key enzymes in both Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS-CoV), offering potential for broad-spectrum treatments.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- Severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS-CoV) are life-threatening coronaviruses.
- MERS-CoV has a high mortality rate, posing a significant global health threat.
Purpose of the Study:
- To develop novel antiviral agents targeting SARS-CoV and MERS-CoV.
- To identify compounds with inhibitory activity against the 3CL protease (3CLpro) of these viruses.
Main Methods:
- Synthesis of analogues based on a neuraminidase (NA) inhibitor scaffold.
- In vitro testing for inhibitory activity against 3CLpro.
- Molecular docking studies to understand binding interactions.
Main Results:
- Identified compounds with low micromolar inhibitory activity against SARS-CoV and MERS-CoV 3CLpro.
- Docking studies revealed that carboxylates destabilize the 3CLpro oxyanion hole.
- Compounds 3f, 3g, and 3m demonstrated dual inhibition of NA and 3CLpro.
Conclusions:
- The identified compounds are effective inhibitors of SARS-CoV and MERS-CoV 3CLpro.
- These compounds represent a promising starting point for developing broad-spectrum antiviral drugs.
- Dual NA and 3CLpro inhibitors could offer a novel therapeutic strategy.
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