Mammalian subtilisin/kexin isozyme ski-1: a proprotein...

C - Chemistry – Metallurgy – 12 – N

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C12N 9/64 (2006.01) C07K 14/81 (2006.01)

Patent

CA 2349587

Using RT-PCR and degenerate oligonucleotides derived from the active site residues of subtilisin-kexin-like serine proteinases, we have identified a highly conserved and phylogenetically ancestral human, rat and mouse type-I membrane-bound proteinase called subtilisin-kexin-isozyme-1 (SKI-1). Computer data bank searches reveals that human SKI-1 was previously cloned but with no identified function. A SKI-1 processed fragment is secreted in culture media in a soluble form. In vitro studies suggest that SKI-1 is a Ca2+-dependent serine proteinase exhibiting a wide pH optimum for cleavage of proBDNF. Peptides mimicking SKI-1 cleavages sites are also disclosed. SKI-1 prosegment has an ex vivo inhibitory effect on SKI-1 activity. The prosegment is also processed and secreted in culture media. One of its fragments is found tightly associated with the SKI-1 soluble form. Therapeutic applications for SKI-1 inhibitors are disclosed.

En utilisant RT-PCR et des oligonucléotides dégénérés dérivés des restes du site actif des sérine protéinases de type subtilisine-kexine, nous avons identifié une protéinase ancestrale d'un point de vue phylogénétique hautement conservée liée à une membrane de type 1 d'une souris, d'un rat ou d'un être humain appelée subtilisne-kexine-isozyme-1 (SKI-1). Des recherches dans une banque de données informatisée révèlent que la SKI-1 humaine avait été clonée auparavant mais sans fonction identifiée. Un fragment de SKI-1 traité est sécrété dans des milieux de culture sous forme soluble. Des études In vitro laissent supposer que SKI-1 est une sérine protéinase dépendant de Ca?2+¿-présentant un vaste pH optimal pour la coupure de proBDNF. Des sites de coupure SKI-1 de peptides mimétiques font aussi l'objet de cette invention. Un prosegment SKI-1 a un effet inhibiteur ex vivo sur l'activité de SKI-1. Le prosegment est aussi traité et sécrété dans des milieux de culture, l'un des fragments s'avérant étroitement associé à la forme soluble de SKI-1. Font aussi l'objet de cette invention des applications thérapeutiques pour les inhibiteurs de SKI-1.

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