Journal ArticleDOI
Novel Furin Inhibitors with Potent Anti-infectious Activity
Kornelia Hardes,Gero L. Becker,Yinghui Lu,Sven O. Dahms,Susanne M. Köhler,Wolfgang Beyer,Kirsten Sandvig,Hiroyuki Yamamoto,Iris Lindberg,Lisa Walz,Veronika von Messling,Manuel E. Than,Wolfgang Garten,Torsten Steinmetzer +13 more
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TLDR
The results confirm that the inhibition of furin is a promising strategy for a short‐term treatment of acute infectious diseases.Abstract:
New peptidomimetic furin inhibitors with unnatural amino acid residues in the P3 position were synthesized. The most potent compound 4-guanidinomethyl-phenylacteyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) inhibits furin with a Ki value of 5.5 pM. The derivatives also strongly inhibit PC1/3, whereas PC2 is less affected. Selected inhibitors were tested in cell culture for antibacterial and antiviral activity against infectious agents known to be dependent on furin activity. A significant protective effect against anthrax and diphtheria toxin was observed in the presence of the furin inhibitors. Furthermore, the spread of the highly pathogenic H5N1 and H7N1 avian influenza viruses and propagation of canine distemper virus was strongly inhibited. Inhibitor MI-1148 was crystallized in complex with human furin. Its N-terminal guanidinomethyl group in the para position of the P5 phenyl ring occupies the same position as that found previously for a structurally related inhibitor containing this substitution in the meta position, thereby maintaining all of the important P5 interactions. Our results confirm that the inhibition of furin is a promising strategy for a short-term treatment of acute infectious diseases.read more
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Journal ArticleDOI
TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells.
Dorothea Bestle,Miriam Ruth Heindl,Hannah Limburg,Thuy Van Lam van,Oliver Pilgram,Hong M. Moulton,David A. Stein,Kornelia Hardes,Kornelia Hardes,Markus Eickmann,Olga Dolnik,Cornelius Rohde,Hans-Dieter Klenk,Wolfgang Garten,Torsten Steinmetzer,Eva Böttcher-Friebertshäuser +15 more
TL;DR: It is shown that S can be cleaved by the proprotein convertase furin at the S1/S2 site and the transmembrane serine protease 2 (TMPRSS2) at theS2′ site, and this approach has considerable therapeutic potential for treatment of COVID-19.
Journal ArticleDOI
Unusual Amino Acids in Medicinal Chemistry.
TL;DR: This Perspective highlights the diversity of unnatural amino acid structures found in hit-to-lead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.
Journal ArticleDOI
The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases
TL;DR: The targeting of PCs for inhibition may result in a useful strategy to treat infections with some highly pathogenic viruses.
Journal ArticleDOI
The proprotein convertase furin in tumour progression.
TL;DR: This review summarise the expression and function of furin in different cancer types, discuss its role in processing cancer‐related proproteins and give examples of potential therapeutic approaches that take advantage of the proteolytic activity offurin in cancer cells.
Posted ContentDOI
TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets
Dorothea Bestle,Miriam Ruth Heindl,Hannah Limburg,Thuy Van Lam van,Oliver Pilgram,Hong M. Moulton,David A. Stein,Kornelia Hardes,Markus Eickmann,Olga Dolnik,Cornelius Rohde,Stephan Becker,Hans-Dieter Klenk,Wolfgang Garten,Torsten Steinmetzer,Eva Böttcher-Friebertshäuser +15 more
TL;DR: It is demonstrated that both TMPRSS2 and furin are essential for SARS-CoV-2 activation in human airway cells and are promising drug targets for the treatment of COVID-19 either by targeting one of these proteases alone or by a combination of furin and TMPR SS2 inhibitors.
References
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