A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin. Issue 41 (24th August 2016)

• Record Type: Journal Article
• Authors: Strack, Martin; Bedini, Andrea; Yip, King T.; Lombardi, Sara; Siegmund, Daniel; Stoll, Raphael; Spampinato, Santi M.; Metzler‐Nolte, Nils
• Is Part Of: Chemistry. Volume 22:Issue 41(2016)
• Page Start: 14605
• Page End: 14610
• Publication Date: 2016-08-24
• Subjects: bioorganometallic chemistry -- metal–peptide conjugates -- opioid receptors -- peptides -- structural biology; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201602432
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Herein, the selective enforcement of one particular receptor‐ligand interaction between specific domains of the μ‐selective opioid peptide dermorphin and the μ opioid receptor is presented. For this, a blocking group scan is described which exploits the steric demand of a bis(quinolinylmethyl)amine rhenium(I) tricarbonyl complex conjugated to a number of different, strategically chosen positions of dermorphin. The prepared peptide conjugates lead to the discovery of two different binding modes: An expected N ‐terminal binding mode corresponds to the established view of opioid peptide binding, whereas an unexpected C ‐terminal binding mode is newly discovered. Surprisingly, both binding modes provide high affinity and agonistic activity at the μ opioid receptor in vitro. Furthermore, the unprecedented C ‐terminal binding mode shows potent dose‐dependent antinociception in vivo. Finally, in silico docking studies support receptor activation by both dermorphin binding modes and suggest a biological relevance for dermorphin itself. Relevant ligand‐protein interactions are similar for both binding modes, which is in line with previous protein mutation studies. Abstract : Decoration of the opioid peptide dermorphin with a spherical organometallic complex at strategically chosen positions resulted in the discovery of a new, unexpected C‐terminal binding mode with exceptionally high affinity to the μ opioid receptor and potent agonistic activity up to the in vivo level (see figure).