title: Leupeptazin, a highly modified tripeptide isolated from cultures of a Streptomyces sp. inhibits cathepsin K.
abstract: Using a human cathepsin K-targeting inhibitor screen, a new leupeptin analogue, leupeptazin (1), containing an unprecedented piperidinotriazine moiety, was isolated from a liquid culture of soil Streptomyces sp. IS2-4 collected in northern Italy. The structure of leupeptazin was established using HRESIMS as well as 1D and 2D NMR data. The inhibitory activity of the compound towards the collagenase cathepsin K was tested in vitro to reveal moderate activity with an inhibition constant, Ki, of 44μM.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Present address: Department of Biochemistry, University of Toronto, 101 College St, TMDT 5-401, Toronto, Ontario M5G 1L7, Canada. Electronic address: natasha.kruglyak@mail.utoronto.ca.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kruglyak
authors.affiliation: Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, 2207 Main Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Henry
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Law
authors.affiliation: Department of Oral, Biological and Medical Sciences, University of British Columbia, 2151 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Kaleta
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Villanueva
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Julian E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, 2207 Main Mall, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada; Department of Oral, Biological and Medical Sciences, University of British Columbia, 2151 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada; Centre for Blood Research, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Electronic address: dbromme@dentistry.ubc.ca.
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
mesh_terms: D056657:Cathepsin K / Q000037:antagonists & inhibitors*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009842:Oligopeptides / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013302:Streptomyces / Q000737:chemistry*
chemical_list: D009842:Oligopeptides; D056657:Cathepsin K
keywords: Leupeptin; Protease inhibition; Streptomyces; Structure elucidation