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Successful combination: virtual screening and cell culture research-Interferon inhibitor discovered

Interferon alpha plays a central role in severe autoimmune disorders. Inhibitors are not available to date. In collaboration with researchers of the ETH Zurich, Switzerland, scientists at the Paul-Ehrlich-Institut have now succeeded in identifying a substance that inhibits interferon alpha release. Their innovative research approach may not only be of significance for the search of an active substance as such but also for the rapid identification of inhibitors of important protein-protein interactions. The journal "Angewandte Chemie" (Applied Chemistry) reports on the research results as an 'epub ahead of print'(Hot Paper; DOI: 10.1002/anie.201105901)

Type I interferons, such as interferon alpha, form part of the innate immune system. Humans would not be viable without them. However, there is a downside to these important messenger substances of our immune system. Thus, constantly elevated interferon alpha levels may cause chronic inflammatory reactions contributing to autoimmune disorders such as Lupus erythematodes. So far, no active substance is available which is able to inhibit interferon release and its effects in a targeted manner. Researchers from a variety of fields of knowledge have united in search of an active substance that inhibits the interaction between the interferon receptor, which is the same for all type I interferons, and interferon alpha: Scientists of the Institute of Pharmaceutical Sciences of the Eidgenössische Technische Hochschule (ETH, Federal Institute of Technology) at Zurich, Switzerland, the head of which is Professor Gisbert Schneider, and immunologists of the Paul-Ehrlich-Institut under the supervision of PD Dr Zoe Waibler, head of one of the temporary research groups of the institute. Dr Schneider and his co-workers screened more than 500,000 substances for their potential ability to bind to a surface area of interferon alpha with the aid of several computer-assisted methods. These methods were used to predict the said surface area as important for the interaction with the receptor. To identify suitable substances, these 3D conformational studies were performed partly with the aid of innovative software methods developed at the ETH at Zurich: "Innovative approaches to computer-aided protein structure analyses have provided us with crucial hints where and how we should search. This study emphasises the tremendous potential of transdisciplinary concepts for active substance research", sayid Schneider.

The six most promising candidate substances were selected and Dr Waibler and her co-workers used them in cell culture assays. For this purpose, the PEI researches used plasmacytoid dendritic cells - the main producers of interferon alpha, which they harvest from bone marrow. Waibler and colleagues had already proved in previous research projects that adding the modified vaccine virus Ankara (MVA) leads to a pronounced interferon alpha response. MVA is a strongly attenuated and thus innocuous pox virus. Two of the six test substances had to be eliminated, due to their insufficient solubility. Among the four remaining ones, however, one of them was a direct hit for the investigators: While the three other substances showed no effects, one of these low molecular chemical compounds efficiently inhibited the production of interferon alpha. "We were ourselves surprised at the incredibly good results obtained from the combination of our two methods", reports Dr Waibler. In other experiments, the PEI investigators proved that the new substance was also able to inhibit interferon alpha release to other danger signals such as other viruses or double-stranded DNA. On the other hand, however, they also identified that at high concentrations of the active substance, a cell-toxic effect developed. The next step therefore is to derive other candidate substances from the leading substance thus discovered, which inhibit receptor binding of interferon selectively and still more specifically, and at the same time, show no toxicity even in high concentrations.

Apart from the concrete search of a new interferon alpha inhibitor, the methodological approach of the two investigators may be of importance. Thanks to the innovative combination of these very differing technologies, many more substances may be found in a short period of time which may be able to inhibit particular protein-protein interactions.

idw :: 16.11.2011

PP Leibniz Graduate School on Aging and Age-Related Diseases (LGSA)
The LGSA is a joint PhD program of the Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) and the Friedrich Schiller University (FSU) in Jena.

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