Johns Hopkins University
A specialized drug screen test using lab-grown human cells has revealed two classes of compounds already in the pharmaceutical arsenal that may work against mosquito-borne Zika virus infections, scientists say.
Zika virus infection in cell death in human forebrain organoids. Image credit: Xuyu Qian, Johns Hopkins University
In a summary of their work, published today in Nature Medicine, the investigators say they screened 6,000 existing compounds currently in late-stage clinical trials or already approved for human use for other conditions. The screening process identified several compounds that showed the ability to hinder or halt the progress of the Zika virus in lab-grown human neural cells.
The research collaboration includes teams from the Johns Hopkins University School of Medicine, the National Institutes of Health, and Florida State University.
“It takes years, if not decades, to develop a new drug,” says Hongjun Song, director of the Stem Cell Biology Program in the Institute of Cell Engineering at Johns Hopkins. “In this sort of global health emergency, we don’t have that kind of time.”
Adds Guo-li Ming, professor of neurology at JHU’s School of Medicine: “Instead of using new drugs, we chose to screen existing drugs. In this way, we hope to create a therapy much more quickly.”
The current outbreak of Zika, which began in South America last year, is known to be responsible for an increase in cases of microcephaly—a severe birth defect in which afflicted infants are born with underdeveloped brains. In the continental United States, there have been a total of 2,260 reported cases of Zika. Though most cases are associated with travel, 43 cases of local transmission have been reported in Florida, in the Miami area. In addition, Puerto Rico has reported 7,855 locally transmitted cases, spurring the Obama administration to declare a public health emergency in the territory on Aug. 12.
The Zika virus is commonly transmitted from mosquito bites or from an infected person to an uninfected person through sexual contact. Despite the potential effects of infection, only one in four infected people will present symptoms if Zika infection, allowing the virus to spread rapidly in areas with local transmission. Because of this, the CDC recommends all pregnant women with ongoing risk of Zika infection, including residence or frequent travel to areas with active Zika virus transmission, receive screening throughout their pregnancy.
Many research groups are fast tracking the development of vaccines, treatments, and mosquito-control measures to combat further spread of the virus.
The new findings are an extension of previous work by the same research team, which found that Zika mainly targets specialized stem cells that give rise to neurons in the brain’s outer layer, the cortex. The researchers observed Zika’s effects in two- and three-dimensional cell cultures called “mini-brains,” which share structures with the human brain and allow researchers to study the effects of Zika in a more accurate model for human infection.
In the current study, the research team exposed similar cell cultures to the Zika virus and the drugs one at a time, measuring for indicators of cell death, including caspase-3 activity, a chemical marker of cell death, and ATP, a molecule whose presence is indicative of cell vitality.
Typically, after Zika infection, the damage done to neural cells is “dramatic and irreversible,” says Hengli Tang, professor of biological sciences at Florida State University. However, some of the compounds tested allowed the cells to survive longer and, in some cases, fully recover from infections.
Further analysis of the surviving cells, Ming says, showed that the promising drugs could be divided into two classes: neuroprotective drugs, which prevent the activation of mechanisms that cause cell death; and antiviral drugs, which slow or stop viral infection or replication.
Overall, Song says, three drugs showed robust enough results to warrant further study:
PHA-690509, an investigational compound with antiviral properties
emricasan, now in clinical trials to reduce liver damage from hepatitis C virus and shown to have neuroprotective effects
niclosamide, a drug already used in humans and livestock to combat parasitic infections, which worked as an antiviral agent in these experiments
Song cautioned that the three drugs “are very effective against Zika in the dish, but we don’t know if they can work in humans in the same way.” For example, he says, although niclosamide can safely treat parasites in the human gastrointestinal tract, scientists have not yet determined if the drug can even penetrate the central nervous system of adults or a fetus inside a carrier’s womb to treat the brain cells targeted by Zika.
Nor, he says, do they know if the drugs would address the wide range of effects of Zika infection, which include microcephaly in fetuses and temporary paralysis from Guillain-Barre syndrome in adults.
“To address these questions, additional studies need to be done in animal models as well as humans to demonstrate their ability to treat Zika infection,” Ming says. “So we could still be years away from finding a treatment that works.”
The researchers say their next steps include testing the efficacy of these drugs in animal models to see if they have the ability to combat Zika in vivo.
See the full article here .
YOU CAN HELP FIND A CURE FOR THE ZIKA VIRUS.
There is a new project at World Community Grid [WCG] called OpenZika.
Zika depiction. Image copyright John Liebler, http://www.ArtoftheCell.com
WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the OpenZika project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.
This project is directed by Dr. Alexander Perryman a senior researcher in the Freundlich lab, with extensive training in developing and applying computational methods in drug discovery and in the biochemical mechanisms of multi-drug-resistance in infectious diseases. He is a member of the Center for Emerging & Re-emerging Pathogens, in the Department of Pharmacology, Physiology, and Neuroscience, at the Rutgers University, New Jersey Medical School. Previously, he was a Research Associate in Prof. Arthur J. Olson’s lab at The Scripps Research Institute (TSRI), where he ran the day-to-day operations of the FightAIDS@Home project, the largest computational drug discovery project devoted to HIV/AIDS, which also runs on WCG. While in the Olson lab, he also designed, led, and ran the largest computational drug discovery project ever performed against malaria, the GO Fight Against Malaria project, also on WCG.
Please help promote STEM in your local schools.
Stem Education Coalition
The Johns Hopkins University opened in 1876, with the inauguration of its first president, Daniel Coit Gilman. “What are we aiming at?” Gilman asked in his installation address. “The encouragement of research … and the advancement of individual scholars, who by their excellence will advance the sciences they pursue, and the society where they dwell.”
The mission laid out by Gilman remains the university’s mission today, summed up in a simple but powerful restatement of Gilman’s own words: “Knowledge for the world.”
What Gilman created was a research university, dedicated to advancing both students’ knowledge and the state of human knowledge through research and scholarship. Gilman believed that teaching and research are interdependent, that success in one depends on success in the other. A modern university, he believed, must do both well. The realization of Gilman’s philosophy at Johns Hopkins, and at other institutions that later attracted Johns Hopkins-trained scholars, revolutionized higher education in America, leading to the research university system as it exists today.