Volume 14, Issue 6 p. 673-685
Full Paper

Design, Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin

Thuy Van Lam van

Thuy Van Lam van

Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, Germany

Search for more papers by this author
Dr. Teodora Ivanova

Dr. Teodora Ivanova

Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, Germany

Search for more papers by this author
Dr. Kornelia Hardes

Dr. Kornelia Hardes

Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, Germany

Search for more papers by this author
Miriam Ruth Heindl

Miriam Ruth Heindl

Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, 35043 Marburg, Germany

Search for more papers by this author
Dr. Rory E. Morty

Dr. Rory E. Morty

Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

Search for more papers by this author
Prof. Eva Böttcher-Friebertshäuser

Prof. Eva Böttcher-Friebertshäuser

Institute of Virology, Philipps University, Hans-Meerwein-Str. 2, 35043 Marburg, Germany

Search for more papers by this author
Prof. Iris Lindberg

Prof. Iris Lindberg

Department of Anatomy and Neurobiology, University of Maryland Medical School, Baltimore, MD, 21201 USA

Search for more papers by this author
Dr. Manuel E. Than

Dr. Manuel E. Than

Protein Crystallography Group, Leibniz Institute on Aging—Fritz Lipmann Institute, Beutenbergstr. 11, 07745 Jena, Germany

Search for more papers by this author
Dr. Sven O. Dahms

Dr. Sven O. Dahms

Department of Biosciences, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria

Search for more papers by this author
Prof. Torsten Steinmetzer

Corresponding Author

Prof. Torsten Steinmetzer

Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032 Marburg, Germany

Search for more papers by this author
First published: 25 January 2019
Citations: 26

Graphical Abstract

Blocking viral activation: A crystal structure of a hexapeptide in complex with furin served as template for the design of new macrocyclic inhibitors. Several compounds inhibit furin with Ki values in the low nanomolar or sub-nanomolar range. Crystal structures in complex with furin could be determined for several analogues. Compared with our linear inhibitors, negligible antiviral efficacy against respiratory syncytial virus was found for the cyclic derivatives.

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.

Conflict of interest

The authors declare no conflict of interest.