Leupeptazin, a highly modified tripeptide isolated from cultures of a Streptomyces sp. inhibits cathepsin K

Natasha Kruglyak; David E Williams; Henry Chen; Simon Law; Jadwiga Kaleta; Ivan Villanueva; Julian E Davies; Raymond J Andersen; Dieter Brömme

doi:10.1016/j.bmcl.2017.02.007

Leupeptazin, a highly modified tripeptide isolated from cultures of a Streptomyces sp. inhibits cathepsin K

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1397-1400. doi: 10.1016/j.bmcl.2017.02.007. Epub 2017 Feb 5.

Authors

Natasha Kruglyak¹, David E Williams², Henry Chen³, Simon Law³, Jadwiga Kaleta⁴, Ivan Villanueva⁵, Julian E Davies⁵, Raymond J Andersen², Dieter Brömme⁶

Affiliations

¹ 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.
² Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, 2207 Main Mall, Vancouver, British Columbia V6T 1Z4, Canada.
³ Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
⁴ Department of Oral, Biological and Medical Sciences, University of British Columbia, 2151 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada.
⁵ Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
⁶ 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.

PMID: 28228366
DOI: 10.1016/j.bmcl.2017.02.007

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, K_i, of 44μM.

Keywords: Leupeptin; Protease inhibition; Streptomyces; Structure elucidation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cathepsin K / antagonists & inhibitors*
Humans
Magnetic Resonance Spectroscopy
Oligopeptides / pharmacology*
Spectrometry, Mass, Electrospray Ionization
Streptomyces / chemistry*

Substances

Oligopeptides
Cathepsin K

Grants and funding

MOP-178822/CIHR/Canada