Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin

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.