The human Y receptor is overexpressed in breast tumour cells and is, therefore, a valuable target for site-selective drug delivery. The well-established hY R-selective ligand [Phe7,Pro34]NPY has been used to couple to drugs but its length of 36 amino acids also implies complex synthesis and high production costs. Therefore, shorter ligands are desirable. However, truncated versions of neuropeptide Y (NPY) usually result in reduced binding, antagonists, or only partial G-protein-biased agonists. Herein, we report on a nonamer peptide derived from the C terminus of NPY that is modified by a carbaborane, which is able to activate hY R fully in terms of G-protein activation but also arrestin recruitment and internalisation. We provide evidence that this unique behaviour is due to the bulky nature of the carbaborane cluster, which might address a specific second binding pocket in hY R that is crucial for arrestin recruitment. Thus, this study helps in deciphering ligand-induced onset of different pathways in hY R mediated signalling.
The front cover picture shows the C‐terminal part of neuropeptide Y, which is N‐terminally modified with a carbaborane cluster (hammer) that can activate and internalize its cognate G protein‐coupled receptor hY1R (cylindric shape) into the cell (shape‐sorter toy). hY1R is of high therapeutic interest as it is involved in a number of pathologies like obesity or cancer. Therefore, truncated NPY analogues are desirable for use as drugs against these conditions. However, C‐terminal fragments of NPY often end up being antagonists or very weak, partial agonists that solely induce G protein signalling but no internalization, a prerequisite for, for example, drug shuttle systems. We discovered that substitution of the N terminus of such a fragment with a lysine carrying a bulky, hydrophobic moiety like a carbaborane leads to full hY1R selective agonism and most importantly induces internalization. More information can be found in the full paper by K. Bellmann‐Sickert et al. on page 2300 in Issue 21, 2018 (DOI: 10.1002/cbic.201800343).
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