A new antiviral drug candidate attacks the Zika virus where it may be most vulnerable—the lipid membrane, which envelopes Zika’s RNA payload. The drug candidate is an engineered peptide that punctures the membrane, directly stopping the Zika virus particle by rupturing it, rather than interfering in Zika’s replication. Even better, the peptide, as demonstrated in tests on mice, can cross the nearly impenetrable blood-brain barrier. Protecting against Zika in the brain is of critical importance, given Zika’s targeting of the brain and central nervous system.
The peptide was developed by scientists based at Nanyang Technological University (NTU), Singapore, in collaboration with colleagues at the Federal University of Minas Gerais, Brazil, and Ghent University, Belgium. When these scientists administered the peptide to Zika-infected mice in the lab, they succeeded in reducing disease symptoms and the number of deaths.
Detailed findings appeared October 22 in the journal Nature Materials, in an article titled, “Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide.” The article suggests that the new “bubble bursting” approach could be useful against a range of membrane-enveloped viruses, not just Zika.
“Therapeutic treatment protected against mortality and markedly reduced clinical symptoms, viral loads, and neuroinflammation, as well as mitigated microgliosis, neurodegeneration, and brain damage,” the article’s authors reported. “In addition to controlling systemic infection, the peptide crossed the blood–brain barrier to reduce viral loads in the brain and protected against Zika-virus-induced blood–brain barrier injury.”
The lab tests showed that when the peptide was administered, 10 out of 12 infected mice survived. In comparison, all the mice in the control group died within a week post-infection. In addition, therapeutic concentrations of the peptide were able to cross the blood–brain barrier, allowing it to inhibit viral infection in the brain.
“There are currently no vaccines for the Zika virus, while available medicines only alleviate symptoms such as fever and pain,” says Nam-Joon Cho, the senior author of the current study and an associate professor at NTU’s School of Materials Science and Engineering. “This newly created peptide holds great promise in becoming a future antiviral drug that can act directly on viral infections in the brain.”
The Zika virus is transmitted by Aedes mosquitoes and infections during pregnancy are linked to birth defects such as microcephaly, a condition in which a baby is born with an abnormally small head and brain. The World Health Organization declared the Zika disease an international emergency in 2016, and it remains a large threat globally today.
In general, most antiviral drugs target the replication process of viruses. However, viruses often mutate quickly and antiviral drugs that target viral replication can become obsolete. Attacking the physical structure of enveloped viruses is a new approach to developing antiviral drugs. It offers promise for the peptide to be effective even if the Zika virus attempts to mutate.
“There are instances where a virus mutation can lead to an epidemic in a short time, leaving communities unprepared,” Cho notes. “By targeting the lipid membrane of virus particles, scientists may devise more robust and effective ways to stop viruses.”
“The peptide differentiates between Zika viral membranes and mammalian cell membranes because the virus particles are much smaller and more curved, while the mammalian cells are larger and flatter,” Cho adds. “Like how a pin pricks a balloon, the peptide pricks a hole in the viral membrane. Prick enough holes, and the virus will be ruptured.”
The Zika virus belongs to the Flaviviridae family and is related to other mosquito-borne viruses like dengue, chikungunya, and yellow fever. As all flaviviruses have virus particles that are around 40 to 55 nanometers in diameter and are enveloped by a lipid membrane, the peptide engineered by the scientists from NTU has the potential to work against these viruses too.
Laboratory tests in this study confirm this potential and in future, the research team intends to study the effects of the peptide on diseases caused by these other viruses in greater detail. The team will also conduct trials in larger animals, and subsequently will plan to initiate human clinical trials, once relevant preclinical studies have been completed and regulatory approvals obtained.