title: 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.
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.
authors.affiliation: Chair of Inorganic Chemistry I, Bioinorganic Chemistry, Ruhr University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Strack
authors.affiliation: Department of Pharmacy and Biochemistry, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bedini
authors.affiliation: Biomolecular NMR, Ruhr University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany.
authors.forename: King T
authors.initials: KT
authors.lastname: Yip
authors.affiliation: Department of Pharmacy and Biochemistry, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lombardi
authors.affiliation: Chair of Inorganic Chemistry I, Bioinorganic Chemistry, Ruhr University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Siegmund
authors.affiliation: Biomolecular NMR, Ruhr University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Stoll
authors.affiliation: Department of Pharmacy and Biochemistry, University of Bologna, Via Irnerio 48, Bologna, Italy.
authors.forename: Santi M
authors.initials: SM
authors.lastname: Spampinato
authors.affiliation: Chair of Inorganic Chemistry I, Bioinorganic Chemistry, Ruhr University Bochum, Universitaetsstrasse 150, 44801, Bochum, Germany. nils.metzler-nolte@rub.de.
authors.forename: Nils
authors.identifier: http://orcid.org/0000-0001-8111-9959
authors.initials: N
authors.lastname: Metzler-Nolte
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D056831:Coordination Complexes; D008024:Ligands; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; C030058:dermorphin; D012211:Rhenium
keywords: bioorganometallic chemistry; metal-peptide conjugates; opioid receptors; peptides; structural biology