Identification of Small Molecules as Zika Virus Entry Inhibitors

TL;DR

This paper identifies a small molecule that effectively inhibits Zika virus entry into cells, offering a potential new treatment for the virus.

Contribution

The study introduces Pyrimidine-Der1 as a novel Zika virus entry inhibitor identified through virtual screening and validated experimentally.

Findings

Pyrimidine-Der1 efficiently inhibits reporter and authentic Zika virus infection with an IC50 of ~3–5 μM.

The compound binds to the Zika virus envelope protein and inhibits infection at the entry and fusion stages.

It shows activity against multiple human Zika virus strains.

Abstract

Zika virus (ZIKV) caused Zika outbreaks and continues to post threats to public health. ZIKV infection may cause congenital abnormalities during pregnancy and neurological manifestations in adults. The recurrent public health threat of Zika in various geographical areas demonstrates a need for the development of effective therapeutics. Currently, there are no approved therapies for Zika. ZIKV is a single-stranded, positive-sense RNA virus, whose genome encodes three structural proteins and seven non-structural proteins. The surface envelope (E) protein is essential for host–cell recognition and viral entry; therefore, inhibition of E-mediated viral entry is a key strategy underlying antiviral treatments. Here, molecular docking-based virtual screening was used to screen small-molecule compound libraries to identify potential ZIKV entry inhibitors. Among the compounds identified, Pyrimidine-Der1 exhibited efficient inhibition of reporter ZIKV infection. The microscale thermophoresis assay confirmed its binding with the ZIKV E protein. This compound has effective inhibition of authentic ZIKV infection in a plaque inhibition assay against R103451, PAN2016, and FLR human strains (IC50: ~3–5 μM). Additionally, it efficiently inhibited ZIKV infection at viral entry and fusion steps of the virus life cycle in a time-of-addition assay. Overall, Pyrimidine-Der1 is a promising ZIKV entry inhibitor, warranting further optimization and evaluation.

Figures