Researchers Identify Strong Drug Candidate for Treatment of Zika Virus
Recent research coming in from Weill Cornell Medicine/Memorial Sloan Kettering suggests that a possible cure for Zika virus may be hiding in plain sight.
*Updated on 7/27/2017 at 1:50 PM EST
Mosquito season is underway in the southern United States, but it is a year-round proposition in certain regions of South America and the Caribbean.
Which is why the lack of an effective treatment for Zika virus infection, the mosquito-borne disease that has plagued Brazil since 2014 and Puerto Rico since 2016—and even appeared in Florida and Texas last summer—remains a confounding clinical challenge. This is despite the fact that the epidemic has, at least in the southern hemisphere, seemingly ended, due at least in part to “herd immunity,” according to experts.
However, recent research performed at Weill Cornell Medicine/Memorial Sloan Kettering and published in the journal Cell Stem Cell suggests that a possible cure may be hiding in plain sight.
For the study, the research team—made up of surgeons, neuroscientists, pharmacologists, and biochemists, among other specialists—screened the Prestwick Library of drug compounds, which includes more than 1,100 medications approved by the US Food and Drug Administration and candidate products, with known bioavailability and safety in humans. They treated human pluripotent stem cell (hPSC)-derived human cortical neural progenitor cells (hNPCs) with each drug for 1 hour before exposing them to Zika virus (MR766 strain) for 2 hours. After culturing the cells for 3 days, the team stained them with antibodies against the Zika envelope protein (ZIKV E) and a cell proliferation marker (Ki67) and then performed quantifications using an automated imaging and analysis system. Compounds that increased total cell number by >100% and suppressed the virus to <20% of controls were considered “positive hits.”
In the end, they identified 9 compounds that significantly inhibit Zika, without inhibiting cell proliferation at 10 μM, and selected the 2 that showed the highest efficacy—the sedative hippeastrine hydrobromide (HH) and the blood pressure medication amodiaquine dihydrochloride dihydrate (AQ)—for further analysis. They found that both effectively inhibited Zika virus infection and “blocked [Zika]-induced growth arrest or apoptosis compared with controls. The drugs also “significantly suppressed the production of viral RNA. Furthermore, transcript profiling revealed that both HH and AQ reversed the “transcriptional changes induced by” Zika, and that treatment of the test cells with 25 μM of HH or 15 μM of AQ “effectively inhibited infection of another [Zika] strain, PRVABC59.”
“We do not know the mechanism of anti-ZIKV effect of hippeastrine hydrobromide or amodiaquine dihydrochloride, [yet],” study coauthor Shuibing Chen, PhD, Associate Professor of Chemical Biology in Surgery at Weill Cornell Medicine told Contagion®. She and her team are currently studying the 2 agents to learn more about their mechanism of action within the setting of the mosquito-borne virus.
After applying the 2 drugs to cell 2 hours post-Zika infection, the authors also found that they eliminated the virus (IC50=3.62 μM for HH and IC50=2.81 μM for AQ), and that HH “successfully rescued [Zika]-induced loss of cell viability with no obvious cytotoxicity.” They then treated Zika-infected hNPCs with HH or AQ for 3 days, and found that both compounds suppressed infection to undetectable levels by day 3. The virus was also undetectable in Zika-infected D20 forebrain organoids treated with HH. In addition, they found that the drug exhibits anti-Zika activity in vivo in the brains of adult mice.
“AQ is approved by FDA as an optional treatment of uncomplicated malaria,” Dr. Chen said. “Since AQ has been reported to have some rare side effects, dose-adjustments and increased safety precautions are required for treatment of patients in order to prevent the intoxication. HH is an active component of Chinese traditional medicine. However, it has not been approved in the United States, which might take some time.”
In their concluding remarks, the authors noted, “Few options are currently available to treat potentially devastating infections from the [Zika] pandemic, but chemical-based drugs may provide a first response option. Our findings suggest a strong drug candidate for the treatment of [Zika virus] infection, in addition to indicating targets for drug development against other flaviviruses, including West Nile virus, Dengue virus, and yellow fever virus, which all cause severe illness.”
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.