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

作者：Strack Martin; Bedini Andrea; Yip King T; Lombardi Sara; Siegmund Daniel; Stoll Raphael; Spampinato Santi M; Metzler Nolte Nils

来源：Chemistry - A European Journal, 2016, 22(41): 14605-14610.

DOI：10.1002/chem.201602432

• bioorganometallic chemistry
• metal-peptide conjugates
• opioid receptors
• peptides
• structural biology

Herein, the selective enforcement of one particular receptor-ligand interaction between specific domains of the -selective opioid peptide dermorphin and the 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 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.

• 出版日期2016-10