A novel bioactive inhibitor of proprotein convertase furin that contains a beta-turn inducing enediyne amino acid

摘要

are responsible for tissue-specific endoproteolytic cleavage of large inactive protein precursors at the general motif(K/R)-(X)_n-(K/R)arrow down,(where n = 0,2,4 or 6 and X is usually not a Cys),generating a large diversity of functionally active proteins and polypeptides in an exquisitely regulated manner.These include hormones,neuropeptides,growth factors,receptors,surface proteins,viral glycoproteins,and bacterial toxins.As a result PCs and furin in particular have been implicated in tumorigenesis,hormonal disorders and a variety of highly infectious diseases including ebola,avian Hong Kong,HIV,human SARS corona viruses and bacterial pathogenesis like anthrax and aerolysin.Owing to these findings we became interested to develop potent and specific inhibitors of furin with therapeutic potentials.Our approach is primarily based on the prodomain sequence of furin which is inhibitory to the cognate enzyme.Herein,for the first time we report that incorporation of a beta-turn inducing aromatic enediyne amino acid(Eda)moiety at the scissile P1-P1' site of a synthetic peptide substrate derived from human pro-domain furin sequence led to the generation of a potent furin-inhibitor with IC_(50)in low nM range.Previously Eda-functions were shown to cleave DNA through their oxidative actions with in situ produced oxygen biradicals.Using a similar strategy but on a peptide frame with sequence compatible with furin recognition,we have developed a novel class of inhibitors for furin.