Variant screening of PYY _3–36 leads to potent long-acting PYY analogs with superior Y ₂ receptor selectivity

Peptide YY (PYY_3-36) has attracted attention in diabetes and obesity research because of its involvement in food intake regulation and glucose homeostasis. Native PYY_3-36 maintains high potency on the Y₂ receptor with a loss of potency on the Y₁, Y₄, and Y₅ receptors. However, PYY_3-36 has a relatively short half-life, and the selectivity displayed by the native peptide may not be optimal if a long-acting analog is to be developed. We performed variant screening of PYY_3-36 to identify key canonical amino acids that are pivotal to Y₂ receptor selectivity, potency, and peptide stability. In combination with fatty diacid derivatization, this afforded highly selective long-acting analogs against the Y₂ receptor, which improved glucose metabolism in diabetic <i>db</i>/<i>db</i> mice. When combined with a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist, these analogs showed superior blood glucose lowering in diabetic ZSF1 rats and greater body weight loss in a high-fat diet-induced mouse model of obesity compared with treatment with the GLP-1 analog alone. One of the tested analogs, PYY1875, has progressed into clinical trials for obesity. Together, our results demonstrate the power of variant screening combined with fatty diacid derivatization in the development of a long-acting, highly efficacious PYY clinical candidate.