Design,Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin |
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Authors: | Thuy Van Lam?van Dr Teodora Ivanova Dr Kornelia Hardes Miriam Ruth Heindl Dr Rory E Morty Prof Eva Böttcher-Friebertshäuser Prof Iris Lindberg Dr Manuel E Than Dr Sven O Dahms Prof Torsten Steinmetzer |
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Affiliation: | 1. Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, Germany;2. Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, 35043 Marburg, Germany;3. Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;4. Department of Anatomy and Neurobiology, University of Maryland Medical School, Baltimore, MD, 21201 USA;5. Protein Crystallography Group, Leibniz Institute on Aging—Fritz Lipmann Institute, Beutenbergstr. 11, 07745 Jena, Germany;6. Department of Biosciences, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria |
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Abstract: | The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad-spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors. Most of the prepared derivatives are relatively potent furin inhibitors with inhibition constants in the low nanomolar or even sub-nanomolar range. For seven derivatives the crystal structures in complex with furin could be determined. In three complexes, electron density was found for the entire inhibitor. In the other cases the structures could be determined only for the P6/P5-P1 segments, which directly interact with furin. The cyclic derivatives together with two non-cyclic reference compounds were tested as inhibitors of the proteolytic activation and replication of respiratory syncytial virus in cells. Significant antiviral activity was found for both linear reference inhibitors, whereas a negligible efficacy was determined for the cyclic derivatives. |
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Keywords: | furin inhibitors macrocyclization proprotein convertases respiratory syncytial virus X-ray crystallography |
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