Using aza-proline for the assembly of a melanostatin aza-peptide derivative

Due to their biochemical nature, bioactive peptides possess a short biological half-life and thus are generally not suitable to be used as pharmaceuticals. By incorporating aza-amino acid residues in biologically active peptides, the stability and bioavailability of peptide drugs are increased as a result of resistance towards peptidases.

Melanostatin is an endogenous hypothalamic neuropeptide with the potential to be used as a treatment for Parkinson’s disease. Pharmacologically, this peptide binds to dopamine D₂ receptors (D₂R) and acts as a positive allosteric modulator (PAM), decreasing the amount of dopamine needed to activate them. Since the D₂R are involved in the aetiology of Parkinson’s disease, the development of potent PAM for these receptors is considered to be a good alternative to reduce the dependence on levodopa therapy, which has major side effects.

In this work, it is reported the preparation of aza-proline and its incorporation in Melanostatin neuropeptide for the assembly of the correspondent aza-peptide derivative. The main goal of this project is to study the influence of the aza-amino acid residue on the biological half-life and PAM activity of Melanostatin. In this sense, this aza-peptide will be evaluated through pharmacological and biological assays to study, respectively, its potency and efficacy as PAM of D₂R and to assess its cytotoxicity. As such, this project is expected to further appraise the application of aza-peptides in the development of novel peptide pharmaceuticals, while studying an alternative treatment for Parkinson’s disease.