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Paritaprevir as a pan-antiviral against different flaviviruses
1Discipline of Natural Sciences, Indian Institute of Information Technology, Design and Manufacturing, Jabalpur, India.
Introduction:
The flavivirus infections caused by the Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV) cause mild to serious pathological conditions, such as fever, joint pain, shock, internal bleeding, organ failure, nausea, breathlessness, brain tissue damage, neurodegenerative diseases, and deaths. As currently no efficient vaccine or drug is available to prevent or treat these diseases in humans, it is essential to identify potential drug-like molecules to treat these diseases. For these reasons, several known anti-viral drugs are repurposed against the proteases of ZIKV, WNV, and DENV to inhibit their activities.
Methods:
The GOLD 5.0 molecular docking program was used to dock 20 HIV and HCV drugs against the ZIKV protease. Based on docking scores, 5 drugs were found to bind to the ZIKV protease with high affinities. Subsequently, the AMBER ff14SB force field was employed to simulate these drug-bound complexes of ZIKV protease. The MM/PBSA free energy method was utilized to compute the binding free energies of these complexes. Consequently, the two best ZIKV protease inhibitors were repurposed against the proteases of DENV and WNV.
Results And Discussion:
It is found that out of the 5 drugs, Ritonavir and Paritaprevir bind to the NS2B-NS3 protease of the ZIKV strongly with the Gibbs binding free energies (∆Gbind) of -17.44±3.18 kcal/mol and -14.25±3.11 kcal/mol respectively. Remarkably, Ritonavir binds to the ZIKV Protease about 12 kcal/mol more strongly compared to its binding to the HIV protease. It is further found that Paritaprevir binds to DENV and WNV proteases as strongly as it binds to the ZIKV protease. Hence it is proposed that Paritaprevir may act as a potent pan-antiviral against the Zika, West Nile, and Dengue viral diseases.
Insights
Repurposing antiviral drugs like Ritonavir and Paritaprevir against Zika, West Nile, and Dengue viruses shows promise. Paritaprevir demonstrates potent pan-antiviral activity, offering a potential treatment for these flavivirus infections.
Area of Science:
- Virology
- Drug Discovery
- Computational Chemistry
Background:
- Flavivirus infections like Zika (ZIKV), Dengue (DENV), and West Nile (WNV) pose significant global health threats.
- Current treatments are limited, necessitating the identification of novel therapeutic agents.
- Viral proteases are critical targets for antiviral drug development.
Purpose of the Study:
- To identify existing antiviral drugs that can inhibit ZIKV, DENV, and WNV proteases.
- To evaluate the binding affinity and efficacy of repurposed drugs against flavivirus proteases.
- To explore potential pan-antiviral agents for treating multiple flavivirus infections.
Main Methods:
- Molecular docking using GOLD 5.0 to screen 20 HIV and HCV drugs against ZIKV protease.
- Molecular dynamics simulations using AMBER ff14SB force field for drug-bound complexes.
- Binding free energy calculations using the MM/PBSA method.
Main Results:
- Five drugs exhibited high binding affinities to the ZIKV protease.
- Ritonavir and Paritaprevir showed strong binding to the ZIKV NS2B-NS3 protease.
- Paritaprevir demonstrated potent binding to DENV and WNV proteases, suggesting pan-antiviral activity.
Conclusions:
- Ritonavir and Paritaprevir are effective inhibitors of ZIKV protease.
- Paritaprevir shows potential as a broad-spectrum antiviral agent against ZIKV, DENV, and WNV.
- Drug repurposing offers a viable strategy for developing new treatments for flavivirus diseases.
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