Cyclic Derivatives of the Chemerin C-Terminus as Metabolically Stable Agonists at the Chemokine-like Receptor 1 for Cancer Treatment

SIMPLE SUMMARY: The innate immune system is a key player in the fight against tumors and metastasis. Chemerin induces the migration of immune cells towards sites of inflammation and is crucial for recruiting natural killer cells towards cancerous tissue. Several cancer types are able to evade the immune system by downregulating levels of chemerin in their environment, which is often associated with decreased patient survival. Treatment with chemerin could counteract this strategy and thus be beneficial for cancer immunotherapy. Here, we report on the design of small synthetic peptides derived from chemerin that are biologically active and stable in blood plasma. They could be used to specifically deliver chemotherapeutics to tumors that express the chemokine-like receptor 1 (CMKLR1) or support the immune system in fighting cancer. Thus, they represent promising cancer therapeutics. ABSTRACT: Chemerin is a small chemotactic protein and a modulator of the innate immune system. Its activity is mainly mediated by the chemokine-like receptor 1 (CMKLR1), a receptor expressed by natural killer cells, dendritic cells, and macrophages. Downregulation of chemerin is part of the immune evasion strategy exploited by several cancer types, including melanoma, breast cancer, and hepatocellular carcinoma. Administration of chemerin can potentially counteract these effects, but synthetically accessible, metabolically stable analogs are required. Other tumors display overexpression of CMKLR1, offering a potential entry point for targeted delivery of chemotherapeutics. Here, we present cyclic derivatives of the chemerin C-terminus (chemerin-9), the minimal activation sequence of chemerin. Chemerin-9 derivatives that were cyclized through positions four and nine retained activity while displaying full stability in blood plasma for more than 24 h. Therefore, these peptides could be used as a drug shuttle system to target cancer cells as demonstrated here by methotrexate conjugates.