title: Toward the first class of suicide inhibitors of kallikreins involved in skin diseases.
abstract: The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3-carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds.
authors.affiliation: Sorbonne Universités, UPMC University Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Institut de Biologie Paris Seine , 7 Quai St Bernard, F-75005 Paris, France.
authors.forename: Xiao
authors.initials: X
authors.lastname: Tan
authors.forename: Feryel
authors.initials: F
authors.lastname: Soualmia
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Renard
authors.forename: Isabelle
authors.initials: I
authors.lastname: Kempen
authors.forename: Lixian
authors.initials: L
authors.lastname: Qin
authors.forename: Maurice
authors.initials: M
authors.lastname: Pagano
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Chahrazade
authors.initials: C
authors.lastname: El Amri
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: D003374:Coumarins / Q000494:pharmacology*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D012871:Skin Diseases / Q000188:drug therapy* / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D015842:Serine Proteinase Inhibitors; C400147:KLK5 protein, human; C082472:KLK7 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C485595:matriptase