Mastering the Canonical Loop of Serine Protease Inhibitors Enhancing Potency by Optimising the Internal Hydrogen Bond Network 英文参考文献.docVIP

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Mastering the Canonical Loop of Serine Protease Inhibitors Enhancing Potency by Optimising the Internal Hydrogen Bond Network 英文参考文献.doc

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Mastering the Canonical Loop of Serine Protease Inhibitors Enhancing Potency by Optimising the Internal Hydrogen Bond Network 英文参考文献

MasteringtheCanonicalLoopofSerineProtease Inhibitors:EnhancingPotencybyOptimisingtheInternal HydrogenBondNetwork JoakimE.Swedberg1,SimonJ.deVeer1,KeiC.Sit1,CyrilF.Reboul2,AshleyM.Buckle2,JonathanM. Harris1* 1Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia, 2Department of Biochemistry and Molecular Biology,SchoolofBiomedicalSciences,FacultyofMedicineandVictorianBioinformaticsConsortium,MonashUniversity,Clayton,Victoria,Australia Abstract Background: Canonical serine protease inhibitors commonly bind to their targets through a rigid loop stabilised by an internalhydrogenbondnetworkanddisulfidebond(s).Thesmallestoftheseissunflowertrypsininhibitor(SFTI-1),apotent and broad-range protease inhibitor. Recently, we re-engineered the contact b-sheet of SFTI-1 to produce a selective inhibitor of kallikrein-related peptidase 4 (KLK4), a protease associated with prostate cancer progression. However, modifications in the binding loop to achieve specificity may compromise structural rigidity and prevent re-engineered inhibitorsfromreachingoptimalbindingaffinity. Methodology/PrincipalFindings:Inthisstudy,theeffectofaminoacidsubstitutionsontheinternalhydrogenbonding network of SFTI were investigated using an in silico screen of inhibitor variants in complex with KLK4 or trypsin. Substitutionsfavouringinternalhydrogenbondformationdirectlycorrelatedwithincreasedpotencyofinhibitioninvitro. This produced a second generation inhibitor (SFTI-FCQR Asn14) which displayed both a 125-fold increased capacity to inhibit KLK4 (Ki=0.038660.0060nM) and enhanced selectivity over off-target serine proteases. Further, SFTI-FCQR Asn14 wasstableincellcultureandbioavailableinmicewhenadministeredbyintraperitonealperfusion. Conclusion/Significance:Thesefindingshighlighttheimportanceofconservingstructuralrigidityofthebindingloopin additiontooptimisingprotease/inhibitorcontactswhenre-engineeringcanonicalserineproteaseinhibitors. Citation