title: Peptidyl cyclopropenones: reversible inhibitors, irreversible inhibitors, or substrates of cysteine proteases?
abstract: Peptidyl cyclopropenones were previously introduced as selective cysteine protease reversible inhibitors. In the present study we synthesized one such peptidyl cyclopropenone and investigated its interaction with papain, a prototype cysteine protease. A set of kinetics, biochemical, HPLC, MS, and (13)C-NMR experiments revealed that the peptidyl cyclopropenone was an irreversible inhibitor of the enzyme, alkylating the catalytic cysteine. In parallel, this cyclopropenone also behaved as an alternative substrate of the enzyme, providing a product that was tentatively suggested to be either a spiroepoxy cyclopropanone or a gamma-lactone. Thus, a single family of compounds exhibits an unusual variety of activities, being reversible inhibitors, irreversible inhibitors and alternative substrates towards enzymes of the same family.
authors.affiliation: Department of Chemistry, The Julius Spokojny Bioorganic Chemistry Laboratory, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Meital
authors.initials: M
authors.lastname: Cohen
authors.forename: Uriel
authors.initials: U
authors.lastname: Bretler
authors.forename: Amnon
authors.initials: A
authors.lastname: Albeck
mesh_terms: D000478:Alkylation / Q000187:drug effects; D020134:Catalytic Domain / Q000187:drug effects; D003521:Cyclopropanes / Q000737:chemistry* / Q000494:pharmacology*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010206:Papain / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D003521:Cyclopropanes; D015853:Cysteine Proteinase Inhibitors; C120343:cyclopropenone; D010206:Papain
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