Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B
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Abstract
Zika virus (ZIKV), a member of the Flaviviridae family, causes significant public health concerns through congenital Zika syndrome and Guillain-Barré syndrome, yet no effective anti-ZIKV drugs or vaccines are available. To address this critical need, we conducted phenotypic, cytopathic effect-based, high-throughput screening followed by medicinal chemistry optimization and discovered novel benzamide anti-ZIKV leads. Current best compounds demonstrated superior potency (EC 50 values 40-400 nM, CC 50 > 50 µM) compared to NITD-008, the most potent known anti-ZIKV agent. Time-of-addition assays, resistant virus selection studies, and biophysical binding experiments confirmed that NS4B interference constitutes the primary antiviral mechanism. Notably, resistance mutations mapped to the C-terminus of NS4B, distinct from other flavivirus NS4B inhibitors targeting dengue or yellow fever viruses, revealing novel insights into a critical function of the region. These findings establish NS4B as an Achilles’ heel for flaviviruses and support the development of pan-flavivirus therapeutics targeting this essential viral protein.
AUTHOR SUMMARY
Since its pandemic spread in 2015-2016, Zika virus infection remains a significant public health threat worldwide. The virus can cause severe brain damage in developing babies and serious neurological complications like Guillain-Barré syndrome in adults. Despite these devastating consequences, we currently lack effective medicines or vaccines to prevent the virus from spreading through communities or from mothers to their unborn children. To address this critical gap, we conducted a large-scale screening of chemical compounds and discovered a promising new class of molecules that can effectively stop Zika virus from replication. Using medicinal chemistry techniques, we were able to make these compounds even more potent against the virus.
In follow-up studies, we found that our compounds work by interfering with a specific viral protein called NS4B, which the virus needs to replicate its genome within the cell. Remarkably, other research teams studying related other flaviviruses (e.g., dengue and yellow fever virus) have independently discovered that this same protein is a vulnerable target. Our findings suggest that NS4B represents a universal weakness across the entire flavivirus family, making it an attractive target for developing broad-spectrum antiviral treatments.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/17453112.
This study presents a promising approach to the development of antiviral agents targeting ZIKV. While the identification of the benzamide series as potent inhibitors of NS4B is a significant advancement, further research is needed to fully characterize their mechanism of action, assess the risk of resistance, and evaluate their pharmacokinetic properties. Addressing these areas will be crucial for advancing these compounds into clinical development. For instance, the detailed SAR analysis provides valuable insights into structural factors for antiviral activity, and its specific target selection of NS4B is crucial for studying the replication and assembly of ZIKV. However, it lacks …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/17453112.
This study presents a promising approach to the development of antiviral agents targeting ZIKV. While the identification of the benzamide series as potent inhibitors of NS4B is a significant advancement, further research is needed to fully characterize their mechanism of action, assess the risk of resistance, and evaluate their pharmacokinetic properties. Addressing these areas will be crucial for advancing these compounds into clinical development. For instance, the detailed SAR analysis provides valuable insights into structural factors for antiviral activity, and its specific target selection of NS4B is crucial for studying the replication and assembly of ZIKV. However, it lacks specification in identifying the exact mechanism of action that allows the benzamide series to inhibit the ZIKV replication. Further experimentation into this could clarify the binding interactions between the compounds and NS4B. Additionally, the potential for resistance is also another common concern of all antiviral agents. Here, investigation into the emergence of resistant strains upon prolonged exposure would provide more insights into its long-term efficacy. Preliminary pharmacokinetic profiling and toxicity assessments may also further help confirm this research's suitability for clinical use.
Specific examples for improvement in the preprint include:
Lack of validation into mechanistic evidence (only shown through molecular docking and indirect biochemical assays) of compounds in directly being able to inhibit NS4B, despite clear target
No data are presented on the potential emergence of resistant ZIKV strains
May benefit from possible animal testing (such as mice) to present preclinical in vivo data (preprint only focuses on in vitro)
Lack of detail in discussing pharmacokinetic properties
Competing interests
The author declares that they have no competing interests.
Use of Artificial Intelligence (AI)
The author declares that they did not use generative AI to come up with new ideas for their review.
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