– CycloBeta-NPY
Novel peptides reveal the subtleties of Neuropeptide Y receptor ligands selectivity
Analogues of the C-terminal segment of the hormone neuropeptide Y containing cyclic beta-amino acid replacements for targeted residues were prepared in order to discover new selective ligands for the Y receptor sub-groups Such analogues may serve as vectors of cytotoxic active principles in a new approach to cancer chemotherapy.
When constrained ß-amino acids were incorporated into Neuropeptide Y sequences the peptides showed selectivity as ligands for the Y4 receptor
In humans, the biological effects of the hormone Neuropeptide Y (NPY) family are mediated by four receptor subtypes. Selective ligands for these receptors are of considerable interest, e.g. Y1 ligands are potential anti-cancer drug carriers while Y4 ligands may help control obesity. In this project truncated peptide sequences based on NPY were envisaged in which two key residues were replaced by restricted cyclobutane ?-amino acids.<br />The success of this study required a synthetic access to the unprecedented ?-amino acids. To this end, a photochemical synthetic strategy and chiral resolution protocols were developed, furnishing the requisite molecules in exploitable quantities and in pure form. The target peptide sequences were prepared using these materials and, to date, some of these peptides have been evaluated as ligands for the receptor subtypes, suggesting that the cyclobutane restriction induces a preference for binding to the Y4 receptor subtype. <br />Since basic side-chains of NPY analogues may reversibly link to certain categories of anti-cancer drugs, the affinity of such peptides for Y1 receptors could make these compound useful drug carriers. An evaluation of model compounds revealed that certain drug/carrier combinations can indeed deliver the active principle in physiological conditions.<br />The project has revealed a significant role for NPY analogues which containing restricted amino acids in the search for new therapeutic agents.<br />
The chemical structures of the NPY analogues envisaged for this study incorporated novel, conformationally-restricted cyclobutane ?-amino acids (ACBCs) as key constituents. These valuable compounds are not generally available and some of the proposed amino acids had never been described previously. It was therefore paramount importance to establish a reliable access to these molecular building blocks, and this was the principal contribution of the French partner to the project.
Reliable, expedient and optimized gram-scale synthetic protocols were therefore established using a [2+2] photocycloaddition approach for the construction of the four-membered ring. In this way, various ring-substituted ACBCs were prepared as well as an oxetane analogue. These photochemical methodologies provided the library of ACBCs in racemic form, so two approaches were developed for the preparative-scale resolution of each of these ?-amino acids: temporary diastereoisomeric derivatization using chiral oxazolidinones, and preparative enantiomeric separation using chiral chromatographic techniques.
A further requirement was to render these fragile ACBC components more robust for inclusion in automated peptide synthesis. This was achieved via upstream coupling with the neighboring amino acid of the target sequence to give a stable dipeptide building block in orthogonally protected form.
4-Membered ring molecular structures are of wide scientific interest but are not easy to prepare. The photochemical synthetic methodology developed here allows access to large quantities of multi-functional 4-membered ring molecules of the ß-amino acid family, which are valuable building blocks in organic chemistry. One application is made for the shortest-known synthesis of the natural product oxetin.
Inclusion of these compounds in NPY sequences provides analogues which show a particular affinity for the Y4 receptor subtype of the native peptide, which may be of interest in the control of obesity. Furthermore, peptide sequences based on NPY may serve as drug-carriers to target specific cell types.
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This project has generated four manuscripts describing the development of photochemical synthetic methodologies, for publication in peer-reviewed organic chemistry journals. One of these describes the shortest total synthesis of the natural product oxetin.
Three more manuscripts, of a biological/medicinal chemistry orientation, have emerged dealing with first-round studies of NPY analogues and model compounds as well as the important role played by cyclic ß-amino acids.
In due course, a full paper resuming the full details of the studies on 4-ring analogues of NPY is anticipated. This may be preceded by patent protection, if warranted by the results of the ongoing biological evaluations.
Project coordination
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
Help of the ANR 271,000 euros
Beginning and duration of the scientific project:
- 0 Months
