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Design, synthesis and evaluation of novel ligands of NPY Y1 receptor as potential anti-cancer drug carriers

Objective

Neuropeptide Y (NPY) is a hormone which is the most abundant neuropeptide found in the mammalian central nervous system. It was proved that NPY is implicated in several highly important biological functions such as food intake, vasoconstriction, orexigenic effects, seizures, anxiety, thermogenesis, cardiac hypertrophy, pain modulation and hormone secretion. These activities are mediated by six receptors namely: Y1-Y6. Recently, it was proved that NPY is also involved in breast cancer growth. Experiments have shown that NPY Y1 receptor was expressed mainly in cancer cells, while NPY Y2 receptor was found mostly in healthy cells. Thus, selective ligands of NPY Y1 receptor could be very promising anti-cancer drug carriers, what was already shown in preliminary experiments at the laboratories of the host institutions. There are some known NPY receptors antagonists, both of peptidic (cyclic or linear constrained) and non-peptidic structure. The most promising are constrained linear peptide analogues of C-terminal fragment of NPY with beta-aminocyclopropanecarboxylic acids (beta-ACCs) as foldamers incorporated. However, these compounds exhibit some important disadvantages caused by their chemical reactivity. We propose application of beta-aminocyclopentanecarboxylic acids as peptide structure constraining units in order to obtain NPY Y1 active and selective ligands. Application of these natural amino acids analogues holds the promise to overcome all problems described for beta-ACCs. The synthesis of stereoisomerically pure beta-aminocyclopentanecarboxylic acids analogues of arginine and glutamine, followed by automated synthesis of NPY peptide analogues will give a vast library of potential NPY Y1 ligands. Their activities will be further verified by in vitro experiments and the application as anti-cancer drug carriers will be tested. Moreover, analysis of their conformation in solution will give the possibility to find structure-activity relationships.

Call for proposal

FP7-PEOPLE-IEF-2008
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Coordinator

UNIVERSITAET REGENSBURG
Address
Universitatsstrasse 31
93053 Regensburg
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 85 492,68
Administrative Contact
Christian Blomeyer (Dr.)