title: Adrenomedullin 2.0: Adjusting Key Levers for Metabolic Stability.
abstract: 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.
authors.affiliation: Institut für Biochemie, Universität Leipzig , Brüderstraße 34, 04103 Leipzig, Germany.
authors.forename: Ria
authors.initials: R
authors.lastname: Schönauer
authors.affiliation: Institut für Biochemie, Universität Leipzig , Brüderstraße 34, 04103 Leipzig, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Els-Heindl
authors.affiliation: Institut für Biochemie, Universität Leipzig , Brüderstraße 34, 04103 Leipzig, Germany.
authors.forename: Jan-Patrick
authors.initials: JP
authors.lastname: Fischer
authors.affiliation: Bayer Pharma AG , Aprather Weg 18A, 42113 Wuppertal, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Köbberling
authors.affiliation: Bayer Pharma AG , Aprather Weg 18A, 42113 Wuppertal, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Riedl
authors.affiliation: Institut für Biochemie, Universität Leipzig , Brüderstraße 34, 04103 Leipzig, Germany.
authors.forename: Annette G
authors.initials: AG
authors.lastname: Beck-Sickinger
mesh_terms: D053607:Adrenomedullin / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D004355:Drug Stability; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D015394:Molecular Structure; D058265:Receptors, Adrenomedullin / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058265:Receptors, Adrenomedullin; D053607:Adrenomedullin