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Design, Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin
Author(s) -
Van Lam van Thuy,
Ivanova Teodora,
Hardes Kornelia,
Heindl Miriam Ruth,
Morty Rory E.,
BöttcherFriebertshäuser Eva,
Lindberg Iris,
Than Manuel E.,
Dahms Sven O.,
Steinmetzer Torsten
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800807
Subject(s) - furin , proprotein convertase , chemistry , glycoprotein , protease , biochemistry , stereochemistry , rational design , enzyme , biology , lipoprotein , ldl receptor , cholesterol , genetics
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.