Identification and validation of a potent Chikungunya virus replication inhibitor by researchers at the Shiv Nadar University, Delhi- NCR

SciFocus/MAy 31, 2024/By Srijita Banerjee -- Chikungunya is a viral disease that spreads to humans through infected mosquitoes, particularly Aedes mosquitoes. Most people infected with the Chikungunya virus experience fever, joint pain, muscle aches, headache, and rash. These symptoms can be severe and disabling, though usually not life-threatening. Chikungunya infection can exacerbate pre-existing health issues, leading to more severe outcomes. The primary method of treatment for chikungunya is taking pain relievers and anti-inflammatory drugs using Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen or acetaminophen, which may be used to alleviate fever and joint pain.

No specific antiviral drugs approved for treating chikungunya virus infection have been identified yet. Therefore, given the lack of specific, effective, and safe inhibitors, a group of researchers led by Prof. Deepak Sehgal and his student Akash Sharma at the Shiv Nadar Institution of Eminence, Delhi NCR, aimed to identify a potent inhibitor capable of halting viral replication.?

The team targeted the Chikungunya Virus non-structural protein 3 macrodomain (CHIKV nsP3MD), which has been reported as a potential target for developing antivirals because not only is this domain involved in the multiplication of viruses and, therefore, the ability to cause a rapid infection but also it is conserved in alphaviruses.

Through molecular docking and molecular dynamics (MD) modeling, the team identified a molecule that can stop the growth of the virus, with IUPAC name as N-[2-(5-methoxy-1H-indol-3-yl) ethyl]-2-oxo-1,2-dihydroquinoline-4-carboxamide. This study was published in the FEBS Journal and was entitled “In Silico Identification of Chikungunya Virus Replication Inhibitor Validated Using Biochemical And Cell-Based Approaches.”

In this study, the team conducted a virtual screening of 245532 compounds from the natural product database to shortlist nine compounds for experimental analysis.

The nsP3MD protein from CHIKV was purified, and the binding of small molecules to nsP3MD was detected by the Thermal Shift Assay (TSA). In the microscale thermophoresis binding experiments, the group confirmed the inhibitory molecule that has the strongest interaction with the CHIKV nsP3MD protein.?

Subsequently, the screened inhibitory compounds were validated by checking their effect on active virus replication in cell culture experiments.

The inhibitor was found to arrest? the virus replication in cell culture demonstrating efficacy of the compound.? Summarily this inhibitor could act as a potent-drug against Chikungunya and used? in the treatment after preclinical and clinical studies.

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