title: An enormously active and selective azapeptide inhibitor of cathepsin B.
abstract: The peptidomimetic Z-Arg-Leu-Arg-Agly-Ile-Val-OMe (where Agly means alpha-aza-glycyl, -NHNHCO-) is the strongest (K(i) = 480 pM) and the most selective inhibitor of cathepsin B to date, being approximately 2310 times as active to cathepsin B as to cathepsin K. In this paper we introduce the peptide and seek to rationalize its structure-activity relationships using molecular dynamics (MD) and NMR. It is shown that the -Agly-moiety restrains the peptide backbone to a bent shape, contrary to its parent peptide (with Gly in position 4), having its backbone extended and flexible. This fold is maintained in the plug covalently bound to the cathepsin B Cys29, in compliance with similar bends already observed in two other azapeptides attached to the active sites of cathepsin B. The MD simulation of the Z-Arg-Leu-Arg-Agly approximately cathepsin B complex suggests that, contrary to other potent inhibitors of cathepsin B, the current double Arg(1)/Arg(3) inhibitor, while maintaining the fold is able to form a unique ion cluster involving both Arg residues on the inhibitor part and two acidic Glu171 and Glu245 on the cathepsin B part, thus enhancing the affinity and subsequently the inhibiting power and selectivity of Z-Arg-Leu-Arg-Agly-Ile-Val-OMe to the observed extreme extent.
authors.affiliation: Faculty of Chemistry, University of Gdańsk, Sobieskiego 18, 80-952 Gdańsk, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Wieczerzak
authors.forename: Sylwia
authors.initials: S
authors.lastname: Rodziewicz-Motowidło
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Jankowska
authors.forename: Artur
authors.initials: A
authors.lastname: Giełdoń
authors.forename: Jerzy
authors.initials: J
authors.lastname: Ciarkowski
mesh_terms: D001665:Binding Sites; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D006834:Hydrazines; D009842:Oligopeptides; C010877:carbazic acid; D002403:Cathepsins; D002401:Cathepsin B; C534130:CTSK protein, human; D056657:Cathepsin K