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
Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn
New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.
Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...
At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.
In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...
Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.
K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...
23.09.2016 | Event News
20.09.2016 | Event News
16.09.2016 | Event News
26.09.2016 | Materials Sciences
26.09.2016 | Materials Sciences
26.09.2016 | Materials Sciences