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.