MADSEN, Peter,KJELDSEN, Thomas Børglum,HOEG-JENSEN, Thomas,JAKOBSEN, Palle,TAGMOSE, Tina Møller,GLENDORF, Tine,KODRA, János Tibor,GARIBAY, Patrick William,PETERSEN, Jacob Sten
申请号：
ES09722934
公开号：
ES2609288T3
申请日:
2009.03.13
申请国别(地区):
ES
年份:
2017
代理人:
摘要：
A protease stabilized acylated insulin where the protease stabilized insulin, formally, consists of an insulin not stabilized against proteases where at least two hydrophobic amino acids have been replaced with hydrophilic amino acids, and where said substitutions are located one, two, or three amino acids away from or within two or more protease cleavage sites that are selected from positions B9-10, B10-11, B13-14, B14-15, B24- 25, B25-26, A13-14 and A14-15 of insulin not stabilized against proteases and wherein such insulin stabilized against proteases optionally further comprises one or more additional mutations provided that there is only one lysine residue in stabilized insulin, and wherein the acyl moiety binds to the lysine residue or to an N-terminal position in insulin stabilized against proteases and has the general formula Aci-AA1n-AA2m-AA3p- (I), where n is 0 or an integer in the range of 1 to 3； m is an integer in the range of 1 to 10； p is 0 or an integer in the range of 1 to 10； Aci is a fatty acid or a fatty diacid comprising from about 8 to about 24 carbon atoms； AA1 is a linear or cyclic neutral amino acid residue； AA2 is an acidic amino acid residue； AA3 is a neutral amino acid residue, containing alkylene glycol； the order in which AA1, AA2 and AA3 appear in the formula can be interchanged independently； AA2 can appear several times throughout the formula. The connections between Aci, AA1, AA2 and / or AA3 are amide bonds that, formally, can be obtained by elimination of a hydrogen atom or a hydroxyl group of each one of Aci, AA1, AA2 and AA3； and protease stabilized insulin binding can be from the C-terminus of an AA1, AA2 or AA3 residue on the acyl residue of formula (I) or from one of the side chain (s) ( is) of a residue AA2 present in the rest of formula (I).Una insulina acilada estabilizada frente a proteasas en donde la insulina estabilizada frente a proteasas, formal-mente, consiste en una insulina no estabilizada frente a proteasas en do
