Pharmacists at Jena University develop three new drug candidates against inflammation
It is something like the police force of our body: the immune system. It disables intruding pathogens, it dismantles injured tissue and boosts wound healing. In this form of 'self-defense' inflammatory reactions play a decisive role.
But sometimes the body’s defense mechanism gets out of control and cells or tissues are affected: “Then excessive reactions can occur and illnesses along with them,” Prof. Dr. Oliver Werz of the Friedrich Schiller University Jena says. He gives asthma, rheumatism, arteriosclerosis and cancer as examples: “For many of these diseases there are only few effective therapies without severe side effects.”
But the team of researchers working together with the Jena pharmacist has now developed three active agents which may be able to improve the healing of inflammatory illnesses better in future. The scientists present the potential therapeutic agents in renowned scientific journals. The agents are able to suppress a key enzyme in the body’s own cascade of inflammation.
“The enzyme called 5-LOX plays a pivotal role in the synthesis of so-called leukotrienes, which are part of numerous immunological and inflammatory processes,” Prof. Werz explains. Hence, the effort to prevent the synthesis of leukotrienes has been the focus of international research for inflammatory therapy for a long time. “Thousands of publications on the subject have emerged in the last 30 years,” says Werz. But apart from one exception none of these efforts have made it to the stage of an approved medication. Either the efficacy of the substances was poor or they were accompanied by unwanted side effects.
As a reason behind this, the Jena pharmacist sees the insufficient understanding of cellular regulation of the leukotriene biosynthesis and the lack of knowledge of the molecular mechanisms of agent and target molecule. “Instead of testing a number of substances to see if one of them might show any activity, we took a close look at 5-LOX and tried to find where exactly this enzyme is vulnerable and what the agents, which can interact with our target molecule, should look like," Werz describes the basis-orientated approach.
In this way the scientists of the Jena University together with partners from Austria, Italy, Turkey and Greece, were able to identify three possible agents. So for instance, a so-called benzoquinone proved to be an effective inhibitor of the 5-LOX. This is a substance which is derived from the natural product embelin from the "False Black Pepper“-plant (Embelia ribes). The pharmacists were able to show that this substance fits exactly into the active center of the enzyme and thus blocks its function. “This specifically only happens with 5-LOX," Werz says and stresses that benzoquinone may practically show no side effects.
A related substance of the red-violet natural dye indirubin, called 6-BIO, proved to be similarly promising. For this substance, the Jena researchers were able to clarify the mechanism of action as well: the 6-BIO inhibits the enzyme 5-LOX by blocking receptor sites for other molecules which are necessary for it to work properly. “In addition, 6-BIO also intervenes with the synthesis of additional inflammatory factors – the cytokines implying additional synergistic effects." This is why 6-BIO could for instance be of interest for the therapy of Alzheimer’s disease, in which cytokines are also playing a role.
The third possible active agent from the Jena University’s laboratory does not inhibit the 5-LOX itself, but it deactivates a helper-protein, which the enzyme needs for its effectiveness within the cell. The researchers identified this active agent, a benzimidazole with the short term BRP-7, by a virtual screening in a library consisting of nearly three million substances. "From our point of view all three of the drug candidates are very well suited to a further development as medications,” Prof. Werz summarizes. However, for this, the support of the pharmceutical industry is needed.
Schaible AM et al. Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4-benzoquinone that inhibits 5-lipoxygenase. British Journal of Pharmacology 2014 (DOI:10.1111/bph.12592)
Pergola C et al. Indirubin core structure of glycogen synthase kinase-3 inhibitors as novel chemotype for intervention with 5-lipoxygenase. Journal of Medical Chemistry 2014 (DOI:10.1021/jm401740w)
Pergola C et al. The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-lipoxygenase-activating protein (FLAP). British Journal of Pharmacology 2014 (DOI:10.1111/bph.12625)
Prof. Dr. Oliver Werz
Institute of Pharmacy
Friedrich Schiller University Jena
Philosophenweg 14, 07743 Jena
Phone: ++49 3641 / 949801
Dr. Ute Schönfelder | idw - Informationsdienst Wissenschaft
New study points the way to therapy for rare cancer that targets the young
22.11.2017 | Rockefeller University
Penn study identifies new malaria parasites in wild bonobos
21.11.2017 | University of Pennsylvania School of Medicine
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
22.11.2017 | Business and Finance
22.11.2017 | Physics and Astronomy
22.11.2017 | Physics and Astronomy