Yan Wang a, Yvonne Angell a, Yun Wu b, Yanfen Teng b, Meng Li b, Krishna Kodukula c and Robert Drakas c
a. Department of Peptide Chemistry, ChemPartner SSF;
b. ChemPartner Shanghai;
c. ShangPharma Innovation, 280 Utah Avenue, Suite 250, SSF, CA 94080
Chemerin is an immunomodulating factor secreted in many tissues including the spleen, lymph nodes, adipose tissue and epithelia. It was identified as a ligand of the Chemerin receptor (ChemR23 / CMKLR1), a chemokine like G protein-coupled receptor (GPCR) and induces chemotaxis in natural killer cells, macrophages, and immature dendritic cells. It is secreted as an inactive precursor, pro-chemerin, and is activated by proteolytic removal of amino acids from the c-terminus by proteases such as elastase, cathepsin G, or kallikrein 7. The nonapeptide, chemerin-9, derived from the C-terminus of the processed form of chemerin is also a potent agonist of CMKLR1.
Chemerin is involved in a variety of functions including cell differentiation and has been linked with diverse indications such as inflammation, psoriasis and obesity. However, its mechanism and detailed signaling pathway remain unclear. Also, chemerin and chemerin-9 are rapidly degraded and inactivated in plasma, which has limited their use in in vivo experiments and as potential therapies. There is a need to develop stable and selective molecular tools to accelerate pharmacological analysis of Chemerin–CMKLR1 interactions, better define signaling pathways, and screen in vivo to validate CMKLR1 as a potential therapeutic target.
We carried out multiple peptide modification strategies and tested more than 230 peptides in an SAR study, using human CMKLR1 over-expressed in U2OS cells as our primary assay. A number of potent analogs were identified, among them, two peptides were chosen as lead candidates for further studies. Both analogs showed good metabolic stability and no toxicity. They also had excellent GPCR selectivity during GPCR panel screening at 10 µM concentration.
Thus, these analogs have emerged as useful tools for further interrogation of chemerin’s biological role and as potential lead structures for continued development.