title: 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 (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 (t1/2 > 51 h) and that GP(Me)H - 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, GP(Me)H could be a lead compound for further development of peptidomimetics able to contrast neuroinflammatory processes.
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy. Electronic address: cacciatore@unich.it.
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Fornasari
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Stefano
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Laura Serafina
authors.initials: LS
authors.lastname: Cerasa
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy; Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey.
authors.forename: Hasan
authors.initials: H
authors.lastname: Turkez
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey.
authors.forename: Elanur
authors.initials: E
authors.lastname: Aydin
authors.affiliation: Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretto
authors.affiliation: Department of Medicine and Aging Science, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ferrone
authors.affiliation: Department of Psychological, Health and Territorial Sciences, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Pesce
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: di Giacomo
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Reale
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Costantini
authors.affiliation: Department of Pharmacy, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Di Giovanni
authors.affiliation: Department of Medicine and Aging Science, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Speranza
authors.affiliation: Department of Medicine and Aging Science, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Felaco
authors.affiliation: Department of Medicine and Aging Science, University "G. D'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Patruno
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018696:Neuroprotective Agents; D009842:Oligopeptides; C000611543:glycine-alpha-methyl-proline; D011392:Proline
keywords: Gly-Pro-Arg; Neurodegenerative disease; Neuroinflammation; α-methyl-proline