Enhancement of simeprevir and sofosbuvir anti-ZIKV activity by iNOS-derived NO in vitroFIRST REVIEW ROUND - REVIEWERS' COMMENTSREVIEWERS' COMMENTS.

BACKGROUND

Zika virus (ZIKV) was first identified in the Americas in 2015, with Brazil experiencing a major epidemic marked by teratogenic effects during early pregnancy. Ex vivo studies of microglia from fatal ZIKV-induced microcephaly cases revealed elevated levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO). Direct-acting antivirals (DAAs) have been proposed as potential ZIKV treatments.

OBJECTIVES

This study aimed to investigate the effects of two DAAs, simeprevir and sofosbuvir, on iNOS expression and NO production during in vitro ZIKV infection.

METHODS

Molecular docking analyses were performed to assess the interaction between DAAs and the iNOS enzyme. ZIKV-infected Vero CCL-81 cells were treated with simeprevir or sofosbuvir (10 µmol/L), and iNOS expression, NO production, and cytotoxicity were evaluated.

FINDINGS: Both DAAs demonstrated strong binding affinity to the iNOS active site. Compared with the untreated infected controls, treatment with simeprevir and sofosbuvir significantly upregulated iNOS expression and increased NO production by approximately 60%. No cytotoxic effects were observed under the experimental conditions.

MAIN

CONCLUSIONS

Simeprevir and sofosbuvir not only exhibit antiviral properties but also may enhance the host antiviral response via modulation of the NO pathway, suggesting a dual mechanism of action against ZIKV.