C8 - Development of modulators at the chemokine-like receptor to elucidate its role in obesity

Previously, we were able to identify the binding mode of the chemerin, a 14 kDa adipokine with its receptor CMKLR1 by using Rosetta as a computational design tool. The binding mode is based on results of CMKLR1 mutagenesis studies, substitution of amino acids within the C-terminal nonapeptide as well as identified cyclic peptide agonists. Now, we will screen for antagonists and modulators of CMKLR1 to reveal orthosteric ligands as well as allosteric modulators and potentiators by high throughput screening, rational design and combine the results with computational design.

Fig. 1: Suggested binding mode of chemerin and CMKLR1. The C-terminus of chemerin (orange) exhibits a turn structure that closely fits into the extracellular binding pocket of CMKLR1. As the linker between the C-terminus and the cystatin motif (dark grey) should be very flexible, it allows for a wide range of possible second binding sites.

Fischer TF, Czerniak AS, Weiß T, Zellmann T, Zielke L, Els-Heindl S, Beck-Sickinger AG. Cyclic Derivatives of the Chemerin C-Terminus as Metabolically Stable Agonists at the Chemokine-like Receptor 1 for Cancer Treatment.  Cancers (Basel) . 2021 Jul 27;13(15):3788.

Fischer TF, Czerniak AS, Weiß T, Schoeder CT, Wolf P, Seitz O, Meiler J, Beck-Sickinger AG. Ligand-binding and -scavenging of the chemerin receptor GPR1. Cell Mol Life Sci. 2021 Jul 9.

Sliwoski G, Schubert M, Stichel J, Weaver D, Beck-Sickinger AG, Meiler J. Discovery of Small-Molecule Modulators of the Human Y4 Receptor. PLoS One. 2016; 11:e0157146.

Schubert M, Stichel J, Du Y, Tough IR, Sliwoski G, Meiler J, Cox HM, Weaver CD, Beck-Sickinger AG. Identification and Characterization of the First Selective Y(4) Receptor Positive Allosteric Modulator. J Med Chem. 2017; 60:7605-7612.

*shared Authorship