Some 160 million men and women are infected with Hepatitis C virus (HCV), the most common cause of cirrhosis and cancer of the liver. The present standard therapy is thraught with serious side-effects leading to a cure in only half of the patients. New therapies utilise small molecules that inhibit specific steps in the viral reproduction. However, the pathogen rapidly develops resistance, becoming insensitive to these agents.
HCV-infected cells: green, fat-droplets, in which the virus is being assembled; red, parts of the virus; blue, the liver cell nucleus
TWINCORE / T. Pietschmann
Researchers at the Helmholtz Centre for Infection Research (HZI) in Braunschweig, in collaboration with colleagues from the TWINCORE in Hannover have discovered new drug leads that are also efficient against resistant virus. They present their work in the Journal of Biological Chemistry.
Interferons are used as classic medication against HCV as well as a few other viruses. Some interferons are produced naturally in the body in response to viral infection, others as immune modulators during inflammation. However, therapy with interferon is expensive, takes many months and has undesirable and unpleasant side effects. Hope was generated during the last few years through the development of a new generation of small drugs directed directly to the virus, in particular to those inhibiting the viral protease. These compounds inhibit viral replication by preventing the formation of the functional and structural components that must be cut out a precursor which the HCV virus instructs the host cell to produce in a single ‘block’. This cutting, or processing, is initiated by the viral protease which mutates rapidly, generating resistant variants for which the protease-inhibitors have lost their effectivity.
Scientists from the group of Prof. John Collins at the HZI have succeeded in identifying novel small molecules that are active against HCV. “Our molecules use several sites of action in inhibiting the viral protease. Amongst these one which had not previously been addressed by existing protease inhibitors,” explains Dr. Jonas Kügler, one of the participating scientists from the HZI. “Thus our molecules are effective against resistant virus with the expectation that the development of resistance will be more difficult,” adds his colleague Dr. Stefan Schmelz from the group of Prof. Dirk Heinz. Kügler and Schmelz are the first authors on the publication. This work is a colaboration between the groups of Collins and Heinz and scientists from the TWINCORE, Hannover, in the institute of Prof. Thomas Pietschmann.
The development of the novel inhibitors used an approach which combined two different tactics: In one special iterative enrichment process using ‘empirical selection’, the scientists searched for small proteins that bound specifically to the desired target: the HCV protease. During the second step, suitable candidates were then slightly modified on the basis of ‘rational design’ and thus further optimized for the desired property. This resulted in molecules that have a strong inhibitory effect on the protease when added at a very low concentration. All of the molecules share a novel structural feature which the researchers call a ‘tyrosine-finger’. This binds a region in the viral protease that was not bound by other inhibitors previously investigated.
“We do not expect that these molecules can be directly used for clinical antiviral therapy“ says John Collins. “Our results are, however, of great significance for the development of novel therapeutics effective even on virus resistant to other small inhibitors.” In the continuing race between the virus and the scientists, the researchers have achieved a new head-lead, or should one say a finger that points in the right direction.
Dr. Jan Grabowski | Helmholtz Zentrum
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences