A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses

Abstract

Zika virus (ZIKV), a re-emerging flavivirus associated with neurological disorders, has spread rapidly to more than 70 countries and territories. However, no specific vaccines or antiviral drugs are currently available to prevent or treat ZIKV infection. Here we report that a synthetic peptide derived from the stem region of ZIKV envelope protein, designated Z2, potently inhibits infection of ZIKV and other flaviviruses in vitro. We show that Z2 interacts with ZIKV surface protein and disrupts the integrity of the viral membrane. Z2 can penetrate the placental barrier to enter fetal tissues and is safe for use in pregnant mice. Intraperitoneal administration of Z2 inhibits vertical transmission of ZIKV in pregnant C57BL/6 mice and protects type I or type I/II interferon receptor-deficient mice against lethal ZIKV challenge. Thus, Z2 has potential to be further developed as an antiviral treatment against ZIKV infection in high-risk populations, particularly pregnant women.

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

“…For example, the ZIKV NS2B-NS3 protease inhibitor novobiocin reduces ZIKV RNA load by ≥ 2 logs both in vitro (Vero and Huh-7 cells) and in the blood and tissues of ZIKV-infected mice (Yuan et al, 2017). Our recently described antiviral peptide (Z2 peptide) targeting the stem region of the ZIKV envelope protein to inhibit virus entry into host cells significantly reduced viral RNA load in ZIKV-infected interferon receptor-deficient mice and inhibited vertical transmission of ZIKV in pregnant C57BL/6 mice (Yu et al, 2017). These findings are not unexpected as our mice only received one dose of AR-12 treatment post- Fig.…”

Montelukast, an Anti-asthmatic Drug, Inhibits Zika Virus Infection by Disrupting Viral Integrity

“…ZIKV strain SZ01/2016 (GenBank number: KU866423), which was isolated from a patient who returned from Samoa and was kindly provided by Dr. Cheng-Feng Qin (Deng et al, 2016b); ZIKV strains FLR [#VR1844, American Type Culture Collection (ATCC)] and MR766 (#VR1838, ATCC) obtained from ATCC; DENV-2 kindly provided by Drs. Yunwen Hu and Zhigang Song at the Shanghai Public Health Clinical Center; and YFV strain 17D obtained from Beijing Tiantan Biological Products, Ltd., were all propagated in C6/36 cells as described previously (Yu et al, 2017). The replication-competent vesicular stomatitis virus (VSV) containing an additional viral transcriptional unit coding green fluorescent protein (VSV-GFP) was kindly provided by Dr. Nannan Wu (Wu et al, 2019) and propagated in Vero E6 cells.…”

“…Plaque assay was performed on BHK-21 cells or Vero E6 cells as previously described (Yu et al, 2017). Briefly, BHK-21 or Vero E6 cells were seeded onto cell culture plates and incubated overnight to a confluent monolayer.…”

“…To detect whether montelukast can release the genomic RNA from the flavivirus particles, the RNase digestion assay and quantitative reverse transcription (qRT) PCR were performed as previously described (Lok et al, 2012;Yu et al, 2017). Briefly, montelukast at different concentration was incubated with ZIKV (300 pfu) at 37 • C for 2 h. Then, the RNA released from virus was digested by micrococcal nuclease (New England BioLabs, Rowley, MA, United States) for 1 h at 37 • C. Then, the viral genomic RNA inside the unbroken virus was extracted by using the EasyPure Viral DNA/RNA Kit (Transgen Biotech, Beijing, China) and detected by qRT-PCR using TransScript Green One-…”

“…The first step of ZIKV infection is its attachment to the host cell membrane. A peptide derived from the stem region of E protein of ZIKV blocked the binding of virions to cells via its interaction with E proteins to disrupt the integrity of the viral membrane (Yu et al, 2017). Erythromycin estolate was also found to effectively inhibit ZIKV infection by disrupting the integrity of the viral membrane .…”