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One million € funding for the development of norovirus therapeutics

No. 27c2 | 08/08/2016

Grant Hansman, head of the CHS Research Group noroviruses, has raised funding under the BMBF funding program "Validation of the Technological and Social Innovation Potential of Scientific Research" in the amount of € 1,164,000. Hansman will develop new antiviral Nanobodies in the project, which can be used as a norovirus therapeutics and diagnostics.

Electron micrograph of norovirus virus-like particles (VLPs) and a cartoon representation of a nanobody, termed Nano-85 (orange). Nano-85 binds to the VLPs and causes the VLPs to disassemble.
© Dr. Grant Hansman, DKFZ

Human noroviruses are the dominant etiological agent of outbreaks of acute gastroenteritis and a major cause of sporadic infections. Noroviruses are highly infectious and less than 100 viral particles are sufficient for an infection. Despite the discovery of norovirus more than 40 years ago, there are still no approved vaccines, antivirals, or treatments. Human noroviruses are genetically and antigenically distinct.

Similar to the influenza virus, the norovirus genome is constantly evolving and novel strains emerge every other year that can lead to new epidemics and even pandemics. Human noroviruses cannot be grown robustly in cell culture, which has hampered the development of vaccines and antivirals. The first clinical studies of a norovirus vaccine were only recently, however the results were met with uncertainties, i.e., lower than expected coverage, little cross protection from other strains, and lack of long term-immunity. Nevertheless, the symptoms of gastroenteritis appeared to be slightly reduced in those immunized.

Grant Hansman's group aims at developing antivirals against human norovirus that can reduce infections, treat symptoms, or both. For this purpose, Hansman and colleagues have produced a library of "Nanobodies" that are directed against norovirus particles in order to identify ones that might inhibit norovirus infections.

Nanobodies are antibody fragments, which are composed of a monomeric, variable domain of an antibody. Hansman and colleagues identified one Nanobody (termed Nano-85) that is able to bind to antigenically distinct noroviruses with nanomolar affinities. They also found that Nano-85 binds to a highly conserved region on the virus particle and the binding interaction causes the particles to disassemble. The researchers believe that this region likely plays a central role in the stability of the particles.

The purpose of this proposal is to provide evidence that the binding of Nano-85 to this unique target region inhibits norovirus infections, since the structural integrity of particles is likely needed for replication and infection. As part of this project Hansman and colleagues will further develop Nano-85 and other Nanobodies to bind to murine norovirus with higher affinities. Overall, they will use a multidisciplinary approach to validate the interactions using bioinformatics, X-ray crystallography, molecular biology techniques, and cell culture.

The underlying concept is that Nanobodies directed against the highly conserved region(s) of the viral particles will disrupt infection, thereby reducing virus replication. Hansman will determine these effects, for the first time, in the murine norovirus cell culture system with the ultimate aim of developing antivirals for preclinical trials.

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

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