The findings, reported in ACS Chemical Biology, support using zebrafish as a novel platform for drug development.
In 2007, Charles Hong, M.D., Ph.D., and colleagues described using fish embryos to screen for compounds that interfere with signaling pathways involved in early development — pathways known to play roles in a variety of disease processes. They discovered the compound "dorsomorphin" and demonstrated that it blocked BMP (bone morphogenetic protein) signaling, which has been implicated in anemia, inflammatory responses and bone-related disorders.
But in examining dorsomorphin further, the investigators found that it had other "off-target" effects — it also blocked the VEGF (vascular endothelial growth factor) receptor and disrupted zebrafish blood vessel development, a process called angiogenesis.
"Off-target effects contribute to side effects and limit the therapeutic potential of small molecule signaling inhibitors," said Hong, assistant professor of Medicine and Pharmacology.
To find compounds that were more selective BMP inhibitors (didn't have the off-target effects), Hong and colleagues opted to use their zebrafish drug discovery screen as a drug development/optimization tool.
Craig Lindsley, Ph.D., director of Medicinal Chemistry for the Vanderbilt Program in Drug Discovery, Corey Hopkins, Ph.D., associate director, and their colleagues used the dorsomorphin "backbone" as a starting point to synthesize many different analogs — subtly different dorsomorphin-like compounds.
Then Hong and his team tested these compounds for their effects on zebrafish embryonic development.
"We quickly discovered that the two effects of dorsomorphin could be separated — some analogs only affected patterning and some only affected angiogenesis," Hong said. The investigators biochemically characterized compounds of both types and found very selective and potent BMP inhibitors and selective VEGF inhibitors.
The zebrafish embryo, Hong said, is very good at assessing a compound's selectivity for a certain signaling pathway. Mixed signals from compounds that are not selective (they hit multiple targets) are toxic to the embryo — it "shuts down development."
The team identified a VEGF inhibitor, for example, that outperformed an existing VEGF inhibitor that was being developed for cancer therapy (blocking angiogenesis cuts off the "supply lines" for a growing tumor) but was pulled from development during a Phase III trial.
"If they (the pharmaceutical company) had tested that compound in zebrafish, they would have quickly learned that it wasn't potent or selective," Hong said.
"Using zebrafish is a novel way to do a structure-activity relationship study" — a study that examines a series of analog compounds to determine which is the most selective and most potent, he added.
Traditionally, pharmaceutical companies perform these types of studies in vitro, with isolated proteins or cells. But Hong points out that in vitro studies assess only "one dimension" of the biology. Compounds that have great activity in vitro often fail later because they have poor selectivity or because they do not have chemical properties that make them good drugs (they are not "bioavailable").
"The zebrafish assesses selectivity and bioavailability all at the same time," Hong says. "What the traditional approach takes months to do, the zebrafish does in a day."
Because BMP and VEGF inhibitors have therapeutic potential for a variety of diseases, the investigators will begin to test the drug candidates in mouse models.
Hong praised Vanderbilt leaders for putting into place the drug discovery infrastructure that made the work possible.
"Having medicinal chemists and zebrafish biologists together in the same building really fostered our collaboration," he said. "This kind of collaboration would not be likely at the majority of medical institutions."
The research was supported by the Veterans Administration, the Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders, the National Institutes of Health and the GSK Cardiovascular Research and Education Foundation.
Leigh MacMillan | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy