Structure-Activity Relationships Studies of GRK2 Peptide inhibitors

G protein-coupled receptor kinase 2 (GRK2) regulates cell signaling by promoting agonist-specific desensitization of several metabolism-related GPCRs, including the b-adrenergic receptors, endothelin, and glucose-dependent insulinotropic polypeptides. The upregulation of GRK2 and corresponding desensitization of these metabolism related GPCRs seem play an important role in the onset or progression of diseases such as heart failure, myocardial ischemia, hypertension, Type 2 diabetes and in cell cycle progression. Recent studies suggest that GRK2 participates in the regulatory network controlling cell cycle arrest and survival in such conditions. Understanding of the molecular mechanisms leading to altered GRK2 levels, as well as the identification of GRK2 inhibitors is a very active field of research. As reported in literature, two short peptides KRX107 (GLLRrHS) and KRX124 (GLLRrHSI), derived from HJ loop of GRK2/3 (2), show a positive effect on glucose metabolism in animal models of Type 2 diabetes, increasing insuline sensitivity and improving glucose homeostasis and emerge as a valuable starting point for the development of a novel class of GRK2 inhibitors. Thus, in this communication we report the preliminary results obtained with a small library of short analogues of KRX107 and KRX124.