Long-Acting Lipidated Analogue of Human Pancreatic Polypeptide Is Slowly Released into Circulation

Abstract

The main disadvantages of peptide pharmaceuticals are their rapid degradation and excretion, their low hydrophilicity, and low shelf lifes. These bottlenecks can be circumvented by acylation with fatty acids (lipidation) or polyethylene glycol (PEGylation). Here, we describe the modification of a human pancreatic polypeptide analogue specific for the human (h)Y(2) and hY(4) receptor with PEGs of different size and palmitic acid. Receptor specificity was demonstrated by competitive binding studies. Modifications had only a small influence on binding affinities and no influence on secondary structure. Both modifications improved pharmacokinetic properties of the hPP analogue in vivo and in vitro, however, lipidation showed a greater resistance to degradation and excretion than PEGylation. Furthermore, the lipidated peptide is taken up and degraded solely by the liver but not the kidneys. Lipidation resulted in prolonged action of the hPP analogue in respect of reducing food intake in mice after subcutaneous administration. Therefore, the lipidated hPP analogue could constitute a potential new therapeutic agent against obesity.

Efflux by Small Multidrug Resistance Proteins Is Inhibited by Membrane-interactive Helix-stapled Peptides

“…Peptide Stability in Blood Plasma and Liver HomogenatesStability assays in blood plasma and liver homogenates were performed as previously described with some slight variations (28,29). TAMRA-labeled peptide was dissolved to 10 M in either blood plasma or beef liver homogenate.…”

Towards improved receptor targeting: anterograde transport, internalization and postendocytic trafficking of neuropeptide Y receptors

“…The hY 4 receptor consists of 375 aa and is mainly expressed in the gastrointestinal tract and, to a much lesser extent, in the hippocampus, the hypothalamus and the area postrema, a region with an incomplete blood-brain barrier (Dumont et al , 1998 ;Lindner et al , 2008a ;Bellmann -Sickert et al, 2011 ). There, the Y 4 receptor can receive signals from peripherally-circulating PP and NPY, modulating energy homeostasis and emotional behavior in synergy with the Y 2 receptor Tasan et al , 2009 ).…”

Gut hormones: the future of obesity treatment?

“…Lipidation of human PP (hPP) with palmitic acid increases its anorectic efficacy in mice [74]. PP 1420 is a peptidase resistant analogue of hPP, shown in phase I clinical trials to be well tolerated and to have a longer circulating half-life compared with the endogenous hormone [75].…”