Journal
CHEMMEDCHEM
Volume 12, Issue 8, Pages 613-620Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700108
Keywords
alphaviruses; chikungunya virus; diphtheria toxin; furin; inhibitors; Semliki Forest virus
Categories
Funding
- US National Institutes of Health (NIH) [DA05084]
Ask authors/readers for more resources
Novel elongated and shortened derivatives of the peptidomimetic furin inhibitor phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide were synthesized. The most potent compounds, such as N(carbamidoyl)Arg-Arg-Val-Arg-4-amidinobenzylamide (K-i=6.2pm), contain additional basic residues at the Nterminus 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 K-i values of 2.50 and 1.26nm, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available