Bioengineered Peptides Based on ل1-PDX Structure as Inhibitors of Furin: Design, Synthesis and Comparative Efficacy

Furin is a ca2+ -dependent serine protease which cleaves proprotein substratesat the arg-xaa-(lys/arg)-arg site to generate biologically active proteins. furin’scritical role in many cellular events associated with health disorders such as hiv,sars, anthrax, and influenza as well as cancer has made inhibitors of this enzymeas therapeutic targets. to this date, the most potent inhibitor of furin is thebioengineered serpin (serine protease inhibitors) protein namely α1-pdx. it wasalready demonstrated that the reactive site loop (rsl) of all serpins are primeinteractive domains responsible for their protease inhibitory function. therefore, theobjective of the present study was to develop small peptides with the rsl structureof serpin α1-pdx, as inhibitors of furin activity. fifteen peptides were designed fromreactive site loop structure of α1-pdx (sequences 367-394) with different mutationsin this site, and were synthesized using a solid-phase peptide synthesizer, andcharacterized by maldi-tof mass spectrometry and amino acid analysis. theinhibitory effects of the designed peptides against furin activity were evaluated byspectroflourometry using qvegf-c [abz-qvhsiirrßslp-y(no2)-a-conh2,abz = 2-amino benzoic acid and y(no2) = 3-nitro tyrosine] as substrate. theresults showed that all of the designed peptides inhibit furin activity with differentefficacies in a time and concentration dependent pattern. peptides containing hisor straight alkyl side chain amino acids in positions p2, p3, p6 and p8 have higherefficacy for blocking furin activity in comparison with peptides containing arg orlys in that position. the study further revealed that the peptides inactivate furin ina slow tight binding pattern. our study provides an alternate strategy for developmentof efficient peptide-based inhibitors of proprotein convertases such as furin