Adrenomedullin 2.0: Adjusting Key Levers for Metabolic Stability
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- 作者：Ria Schönauer ; Sylvia Els-Heindl ; Jan-Patrick Fischer ; Johannes Köbberling ; Bernd Riedl ; Annette G. Beck-Sickinger
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：June 23, 2016
- 年：2016
- 卷：59
- 期：12
- 页码：5695-5705
- 全文大小：580K
- 年卷期：0
- ISSN：1520-4804
文摘
The 52 amino acid peptide hormone adrenomedullin (ADM) plays a major role in the development and regulation of the cardiovascular and lymphatic system and has therefore gained significant interest for clinical applications. Because adrenomedullin exhibits low metabolic stability, enhancement of the plasma half-life is essential for peptide-based drug design. Fluorescently labeled ADM analogues synthesized by Fmoc/t-Bu solid phase peptide synthesis were used to analyze their enzymatic degradation and specific fragmentation pattern in human blood plasma. The determination of important cleavage sites allowed the development of selectively modified peptides in a rational approach. By combination of palmitoylation, lactam-bridging, and Nα-methylation, ADM analogues protected from enzymatic cleavage in human blood were developed and revealed an explicitly elongated half-life of 5 days in comparison to the wild-type in vitro. This triple-modification did not alter the selectivity of the analogues at the AM1 receptor, highlighting their potential for therapeutic applications.