Metabolite Screening Identifies Potent Antivirals that Mitigate Zika Virus-Induced Ocular Pathology

Zika virus (ZIKV) infection remains a significant global health threat due to its association with severe congenital, neurological, and ocular complications and the continued lack of approved antiviral therapies or vaccines. To identify new therapeutic candidates, we performed a high-throughput antiviral screen of 1,050 human endogenous and exosome-derived metabolites for their ability to attenuate ZIKV infection in human retinal pigment epithelial cells (RPE). This led to the identification of 10 metabolites that reduced ZIKV-induced cytopathic effects, which were further evaluated for antiviral activity and toxicity using physiologically relevant ocular infection models. Among these candidates, octanedioic acid, undecanedioic acid, and 10-undecen-1-ol emerged as the most effective, significantly reducing ZIKV replication and modulating innate immune responses in RPE cells. Analysis of host signaling revealed metabolite-associated changes in STAT1, AMPK, and YAP phosphorylation, identifying potential pathways tied to their antiviral activity. Importantly, in an immunocompetent mouse model of ZIKV-induced chorioretinal atrophy, treatment with these metabolites markedly reduced retinal lesions and immune cell infiltration, demonstrating in vivo therapeutic efficacy. Collectively, these findings identify host-derived metabolites as promising antiviral candidates against ZIKV and warrant further translational investigation.