A stable meta‐carborane enables the generation of boron‐rich peptide agonists targeting the ghrelin receptor

Abstract

Boron neutron capture therapy (BNCT) is a binary cancer therapy, which combines the biochemical targeting of a boron-containing drug with the regional localization of radiation treatment. Although the concept of BNCT has been known for decades, the selective delivery of boron into tumor cells remains challenging. G protein-coupled receptors that are overexpressed on cancer cells in combination with peptidic ligands can be potentially used as shuttle system for a tumor-directed boron uptake. In this study, we present the generation of short, boron-rich peptide conjugates that target the ghrelin receptor. Expression of the ghrelin receptor on various cancer cells makes it a viable target for BNCT. We designed a novel hexapeptide super-agonist that was modified with different specifically synthesized carborane monoclusters and tested for ghrelin receptor activation. A meta-carborane building block with a mercaptoacetic acid linker was found to be optimal for peptide modification, owing to its chemical stability and a suitable activation efficacy of the conjugate. The versatility of this carborane for the development of peptidic boron delivery agents was further demonstrated by the generation of highly potent, boron-loaded conjugates using the backbone of the known ghrelin receptor ligands growth hormone releasing peptide 6 and Ipamorelin.

Carborane‐Based Analogues of 5‐Lipoxygenase Inhibitors Co‐inhibit Heat Shock Protein 90 in HCT116 Cells

“…For efficient treatment, a concentration of 20–35 μg of the isotope boron‐10 per gram of tumor is required . To ensure tumor‐selective shuttling of high amounts of boron into tumor cells, carboranes have been used in combination with tumor‐selective peptides for targeting the Y 1 or ghrelin receptors . Sugar substituents have been shown to enhance the aqueous solubility of these hydrophobic clusters .…”

“…[7] To ensure tumor-selective shuttlingo fh igh amounts of boron into tumor cells, carboranes have been used in combination with tumor-selective peptides for targeting the Y 1 [8] or ghrelin receptors. [9] Sugar substituents have been shown to enhance the aqueous solubility of these hydrophobic clusters. [10] Furthermore, carboranes are frequently used as phenylm imetics for biologically active compounds.…”

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

“…Modification of a novel hexapeptide super‐agonist at the GhrR with different carborane monoclusters was evaluated and a meta ‐carborane with a mercaptoacetic acid linker was found to be optimal, owing to its high chemical stability and a suitable GhrR activation efficacy of the conjugate. [ 267 ] Introduction of this meta ‐carborane into the known ghrelin receptor ligands GHRP‐6 and Ipamorelin yielded boron‐rich peptide conjugates with high potency that were specifically shuttled into cells by GhrR‐mediated endocytosis.…”

Side Chain Orientation of Tryptophan Analogues Determines Agonism and Inverse Agonism in Short Ghrelin Peptides

“…In IP-One assay,E C 50 valuesof16.4 nm and 228 nm were observed for 18 and 19,respectively.T he EC 50 value of 18 is similar to previous studies. [15] However, a1 0-fold shift has been observed for 19,s imilar to the inverse agonist. In addition, we observed super-agonism for 19 in ar adioactiveI Pa ccumulation assay but not in the Cisbio IPOne assays.W hen Wrf wasi ncluded into AwFn-Isn-NH 2 substituting d-2Nal (20), potency was almost the same as that of 18.T he corresponding Wsf analogue 21 had as lightly lower potencya nd efficacy than 20.…”