Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin.

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 N? (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.

SUBMITTER: Hardes K 

PROVIDER: S-EPMC5572662 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature