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!
Transport of molecular motors into cilia
28.03.2017 | Aarhus University
Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside
The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.
To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
28.03.2017 | Life Sciences
28.03.2017 | Information Technology
28.03.2017 | Physics and Astronomy