Synthesis and Evaluation of Insulin-Human Serum Albumin Conjugates

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• 作者：Karen Thibaudeau ; Roger Lé ; ger ; Xicai Huang ; Martin Robitaille ; Omar Quraishi ; Chantal Soucy ; Nathalie Bousquet-Gagnon ; Pieter van Wyk ; Vé ; ronique Paradis ; Jean-Paul Castaigne ; and Dominiq
• 刊名：Bioconjugate Chemistry
• 出版年：2005
• 出版时间：July 2005
• 年：2005
• 卷：16
• 期：4
• 页码：1000 - 1008
• 全文大小：283K
• 年卷期：v.16,no.4(July 2005)
• ISSN：1520-4812

文摘

A series of human insulin maleimido derivatives with short and long linkers was synthesized byexploiting the variations in the pK_a values and environment of the three amino groups present in theprotein. The syntheses were accomplished in organic solvent because of maleimide's instability inbasic aqueous media. The derivatives thus obtained were conjugated to the free thiol on Cys34 ofhuman serum albumin (HSA) and purified. A structure-activity relationship based on in vitro receptorbinding and activation results for this series of insulin-HSA conjugates showed that the bestcompounds were attached at the B1 position of insulin with either short or long linkers. Two conjugateswere administered subcutaneously to streptozotocin-induced diabetic rats and found to possess bloodglucose normalizing activity up to 8 h postadministration. The return to diabetic plasma glucose levelswas not observed within the time frame of the experiment (48 h). In comparison, the insulin-treatedgroup's normalization activity lasted 2 h and returned to a diabetic level at 8 h. The onset of theconjugate activities were delayed by 1 h when compared to the activity of human insulin. The studyresults led to the identification of CJC-1575 as a potent and long lasting human insulin analogue.