Pharma / Biotech

Half-Life Extending Modifications of Peptide YY3-36 Direct Receptor-Mediated Internalization.

Half-Life Extending Modifications of Peptide YY3-36 Direct Receptor-Mediated Internalization.

Mol Pharm. 2019 Jul 16;:

Authors: Bech EM, Kaiser A, Bellmann-Sickert K, Nielsen SS, Sørensen KK, Elster L, Hatzakis N, Pedersen SL, Beck-Sickinger AG, Jensen KJ

Abstract
Peptide YY3-36 (PYY3-36) is an endogenous ligand of the neuropeptide Y2 receptor (Y2R), on which it acts to reduce food intake. Chemically modified PYY3-36 analogs with extended half-lives are potential therapeutics for the treatment of obesity. Here we show that the common half-life extending strategies PEGylation and lipidation not only control PYY3-36’s pharmacokinetics but also affects central aspects of its pharmacodynamics. PEGylation of PYY3-36 inhibited endocytosis by increasing receptor dissociation rates (koff), which reduced arrestin-3 (Arr3) activity. This is the first link between Arr3 recruitment and Y2R residence time. C16-lipidation of PYY3-36 had negligible impact on Y2R signaling, binding, and endocytosis. In contrast, C18acid-lipidation minimized endocytosis, which indicated a decreased internalization through non-arrestin-related mechanisms. We propose a temporal model that connects properties and position of the half-life extender with receptor Gi versus Arr3 signaling bias. We believe that this will be important for future design of peptide therapeutics.

PMID: 31310716 [PubMed – as supplied by publisher]

Source link

Related posts

Total-body PET and highly stable chelators together enable meaningful 89Zr-antibody-PET studies up to 30 days post-injection.

Newsemia

HYDROXYZINE PAMOATE Capsule [Lake Erie Medical DBA Quality Care Products LLC]

Newsemia

DIABETIC ADVANCED HEALING CREAM (dimethicone) cream [Neoteric Cosmetics, Inc.]

Newsemia

This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More

Privacy & Cookies Policy

COVID-19

COVID-19 (Coronavirus) is a new illness that is having a major effect on all businesses globally LIVE COVID-19 STATISTICS FOR World