Synthesis of tight binding inhibitors and their action on the proprotein-processing enzyme furin

Furin is a subtilisin-like eukaryotic serine endoprotease which processes proproteins to biologically active proteins and peptides. Also, the envelope proteins of viruses, such as influenza and HIV viruses, need to be processed by furin for infectivity. This enzyme has a consensus substrate specificity for Arg-Xxx-Lys/Arg-Arg at the cleavage site. Two kinds of transition state analog peptides were designed and tested in vitro with furin. The ketomethylene series, psi (COCH2), have Ki's in the submicromolar range; the aminomethyl aminomethyl ketone series, psi(COCH2NH), have Ki's in the nanomolar range. The best inhibitor is Dec-Arg-Val-Lys-Arg-CH2-Ala-Val-Gly-NH2 (2c) with a Ki of 3.4 nM.