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

作者：Cacciatore Ivana^*; Fornasari Erika; Di Stefano Antonio; Marinelli Lisa; Cerasa Laura Serafina; Turkez Hasan; Aydin Elanur; Moretto Alessandro; Ferrone Alessio; Pesce Mirko; di Giacomo Viviana; Reale Marcella; Costantini Erica; di Giovanni Pamela; Speranza Lorenza; Felaco Mario; Patruno Antonia

来源：European Journal of Medicinal Chemistry, 2016, 108: 553-563.

DOI：10.1016/j.ejmech.2015.12.003

• alpha-methyl-proline
• Gly-Pro-Arg
• Neurodegenerative disease
• Neuroinflammation

Herein is described the synthesis of novel glycine-alpha-methyl-proline-containing tripeptides (GP(Me)X tripeptides namely GP(Me)R, GP(Me)K, and GP(Me)H) 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 GP(Me)R, GP(Me)K, and GP(Me)H were all achieved both by introducing the Pro(Me) 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 GP(Me)X tripeptides are stable in human plasma (t(1/2) > 51 h) and that GP(Me)H generating stable intramolecular H-bond in a C-11-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, GP(Me)H could be a lead compound for further development of peptidomimetics able to contrast neuroinflammatory processes.

• 出版日期2016-1-27