Recent advances in drug discovery for Zika virus therapeutics

Zika virus (ZIKV) is a mosquito-borne Orthoflavivirus that became a major global health concern following the 2015-2016 outbreaks in South America, where infection was linked to severe neurological outcomes, including microcephaly, congenital Zika syndrome (CZS), and Guillain-Barré syndrome (GBS). Although substantial efforts are underway to develop effective preventive measures, including vaccines and vector-control strategies, ZIKV remains a priority pathogen under the World Health Organization (WHO) R&D Blueprint due to its pandemic potential. This concern is intensified by the expansion of mosquito vectors caused by climate change and the serious outcomes observed in newborns. The severity of ZIKV-related neurological complications highlights the need for research into post-exposure treatments that can reduce long-term effects and improve clinical results. Efforts to identify antiviral molecules, especially strategies like drug repositioning, have highlighted compounds such as nucleoside analogs, which have shown inhibitory effects in preclinical models. Host-targeting approaches have also shown promise, with small-molecule inhibitors and certain organic dyes demonstrating notable antiviral activity in both cell-based and animal models. Furthermore, natural compounds with cytoprotective properties, such as betulinic acid, have emerged as attractive candidates due to their combined antiviral and neuroprotective effects, which may help limit ZIKV-induced pathology. Despite these advances, most evidence remains limited to preclinical research, emphasizing the need for translational and clinical studies that validate the efficacy and safety of these therapeutic strategies, a crucial step toward transforming promising laboratory findings into available, effective treatments.