Illuminating the neuropeptide Y4 receptor and its ligand pancreatic polypeptide from a structural, functional, and therapeutic perspective

The neuropeptide Y₄ receptor (Y₄R), a rhodopsin-like G protein-coupled receptor (GPCR) and the hormone pancreatic polypeptide (PP) are members of the neuropeptide Y family consisting of four receptors (Y₁R, Y₂R, Y₄R, Y₅R) and three highly homologous peptide ligands (neuropeptide Y, peptide YY, PP). In this family, the Y₄R is of particular interest as it is the only subtype with high affinity to PP over NPY. The Y₄R, as a mediator of PP signaling, has a pivotal role in appetite regulation and energy homeostasis, offering potential avenues for the treatment of metabolic disorders such as obesity. PP as anorexigenic peptide is released postprandial from the pancreas in response to food intake, induces satiety signals and contributes to hamper excessive food intake. Moreover, this system was also described to be associated with different types of cancer: overexpression of Y₄R have been found in human adenocarcinoma cells, while elevated levels of PP are related to the development of pancreatic endocrine tumors. The pharmacological relevance of the Y₄R advanced the search for potent and selective ligands for this receptor subtype, which will be significantly progressed through the elucidation of the active state PP-Y₄R cryo-EM structure. This review summarizes the development of novel PP-derived ligands, like Obinepitide as dual Y₂R/Y₄R agonist in clinical trials or UR-AK86c as small hexapeptide agonist with picomolar affinity, as well as the first allosteric modulators that selectively target the Y₄R, e.g. VU0506013 as potent Y₄R positive allosteric modulator or (S)-VU0637120 as allosteric antagonist. Here, we provide valuable insights into the complex physiological functions of the Y₄R and PP and the pharmacological relevance of the system in appetite regulation to open up new avenues for the development of tool compounds for targeted therapies with potential applications in metabolic disorders.