Development of glycine-α-methyl-proline-containing tripeptides with neuroprotective properties

Abstract

Herein is described the synthesis of novel glycine-α-methyl-proline-containing tripeptides (GPMeX tripeptides namely GPMeR, GPMeK, and GPMeH) with the aim of obtaining derivatives highly stable in human plasma and able to counteract neuroinflammatory processes that are distinctive of neurodegenerative pathologies. The syntheses of GPMeR, GPMeK, and GPMeH were all achieved both by introducing the ProMe residue into the Gly-Pro-Arg (GPR) sequence in place of the native Pro in P2 position and replacing the basic amino acid Arg in P3 position by Lys or His.Results showed that all novel GPMeX tripeptides are stable in human plasma (t1/2 > 51 h) and that GPMeH – generating stable intramolecular H-bond in a C11-turn by interaction of His imidazole ring and Gly carbonyl group – restored physiological levels of nitric oxide deriving from neuronal NOS (nNOS) activity, thus preventing the inflammatory response by suppression of the NF-kB activity and, consequently, the expression of inflammatory genes such as inducibile NOS (iNOS). Therefore, GPMeH could be a lead compound for further development of peptidomimetics able to contrast neuroinflammatory processes.