Adrenomedullin disulfide bond mimetics uncover structural requirements for AM1 receptor activation. (24th January 2019)

• Record Type: Journal Article
• Authors: Fischer, Jan‐Patrick; Schönauer, Ria; Els‐Heindl, Sylvia; Bierer, Donald; Koebberling, Johannes; Riedl, Bernd; Beck‐Sickinger, Annette G.
• Is Part Of: Journal of peptide science. Volume 25:Number 3(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-01-24
• Subjects: adrenomedullin (ADM) -- calcitonin gene‐related peptide (CGRP) superfamily -- disulfide bond mimetics (DSBM) -- G protein‐coupled receptor (GPCR) activation -- peptide cyclization -- solid phase peptide synthesis (SPPS) -- structure‐activity studies; Peptides -- Periodicals; Peptides -- Periodicals; 572.65
• DOI: 10.1002/psc.3147
• Languages: English
• ISSNs: 1075-2617

Abstract

Abstract : Adrenomedullin (ADM) is a vasoactive peptide hormone of 52 amino acids and belongs to the calcitonin peptide superfamily. Its vasodilative effects are mediated by the interaction with the calcitonin receptor‐like receptor (CLR), a class B G protein‐coupled receptor (GPCR), associated with the receptor activity modifying protein 2 (RAMP2) and functionally described as AM‐1 receptor (AM1 R). A disulfide‐bonded ring structure consisting of six amino acids between Cys 16 and Cys 21 has been shown to be a key motif for receptor activation. However, the specific structural requirements remain to be elucidated. To investigate the influence of ring size and position of additional functional groups that replace the native disulfide bond, we generated ADM analogs containing thioether, thioacetal, alkane, and lactam bonds between amino acids 16 and 21 by Fmoc/ t‐ Bu solid phase peptide synthesis. Activity studies of the ADM disulfide bond mimetics (DSBM) revealed a strong impact of structural parameters. Interestingly, an increased ring size was tolerated but the activity of lactam‐based mimetics depended on its position within the bridging structure. Furthermore, we found the thioacetal as well as the thioether‐based mimetics to be well accepted with full AM1 R activity. While a reduced selectivity over the calcitonin gene‐related peptide receptor (CGRPR) was observed for the thioethers, the thioacetal was able to retain a wild–type‐like selectivity profile. The carbon analog in contrast displayed weak antagonistic properties. These results provide insight into the structural requirements for AM1 R activation as well as new possibilities for the development of metabolically stabilized analogs for therapeutic applications of ADM. Abstract : Replacing the disulfide bond: Adrenomedullin exerts its effects by activating the receptors of the calcitonin receptor‐like receptor/receptor activity‐modifying protein system, in particular the AM1 R. Replacement of the functionally important disulfide bond in adrenomedullin with different mimetics led to the identification of two analogs with wild–type‐like AM1 R activity as well as a novel antagonist. Our findings provide valuable structure‐activity insights and will be useful for the development of adrenomedullin‐based therapeutics with enhanced metabolic stability.