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ChemMedChem. 2017 Apr 20;12(8):613-620. doi: 10.1002/cmdc.201700108. Epub 2017 Apr 4.

Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin.

Author information

1
Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, 35032, Marburg, Germany), Fax: (+49) 642-128-259-01.
2
Karolinska Institutet, Department of Microbiology, Tumor and Cell Biology, 171 77, Stockholm, Sweden.
3
Department of Molecular Cell Biology and Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway.
4
Faculty of Engineering Sciences, Hochschule Ansbach, Residenzstraße 8, 91522, Ansbach, Germany.
5
Department of Anatomy and Neurobiology, University of Maryland Medical School, Baltimore, MD, 21201, USA.

Abstract

Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, such as Nα (carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (Ki =6.2 pm), contain additional basic residues at the N terminus and inhibit furin in the low-picomolar range. Furthermore, to decrease the molecular weight of this inhibitor type, compounds that lack the P5 moiety were prepared. The best inhibitors of this series, 5-(guanidino)valeroyl-Val-Arg-4-amidinobenzylamide and its P3 tert-leucine analogue displayed Ki values of 2.50 and 1.26 nm, respectively. Selected inhibitors, together with our previously described 4-amidinobenzylamide derivatives as references, were tested in cell culture for their activity against furin-dependent infectious pathogens. The propagation of the alphaviruses Semliki Forest virus and chikungunya virus was strongly inhibited in the presence of selected derivatives. Moreover, a significant protective effect of the inhibitors against diphtheria toxin was observed. These results confirm that the inhibition of furin should be a promising approach for the short-term treatment of acute infectious diseases.

KEYWORDS:

Semliki Forest virus; alphaviruses; chikungunya virus; diphtheria toxin; furin; inhibitors

PMID:
28334511
PMCID:
PMC5572662
DOI:
10.1002/cmdc.201700108
[Indexed for MEDLINE]
Free PMC Article

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