PREreview del Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B

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.