title: Insights into structure-activity relationships of somatostatin analogs containing mesitylalanine.
abstract: The non-natural amino acid mesitylalanine (2,4,6-trimethyl-L-phenylalanine; Msa) has an electron-richer and a more conformationally restricted side-chain than that of its natural phenylalanine counterpart. Taking these properties into account, we have synthesized ten somatostatin analogs containing Msa residues in different key positions to modify the intrinsic conformational flexibility of the natural hormone. We have measured the binding affinity of these analogs and correlated it with the main conformations they populate in solution. NMR and computational analysis revealed that analogs containing one Msa residue were conformationally more restricted than somatostatin under similar experimental conditions. Furthermore, we were able to characterize the presence of a hairpin at the pharmacophore region and a non-covalent interaction between aromatic residues 6 and 11. In all cases, the inclusion of a D-Trp in the eighth position further stabilized the main conformation. Some of these peptides bound selectively to one or two somatostatin receptors with similar or even higher affinity than the natural hormone. However, we also found that multiple incorporations of Msa residues increased the life span of the peptides in serum but with a loss of conformational rigidity and binding affinity.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona) Baldiri Reixac, 10, Barcelona 08028, Spain. maria.macias@irbbarcelona.org.
authors.forename: Pablo
authors.initials: P
authors.lastname: Martín-Gago
authors.forename: Eric
authors.initials: E
authors.lastname: Aragón
authors.forename: Marc
authors.initials: M
authors.lastname: Gomez-Caminals
authors.forename: Jimena
authors.initials: J
authors.lastname: Fernández-Carneado
authors.forename: Rosario
authors.initials: R
authors.lastname: Ramón
authors.forename: Pau
authors.initials: P
authors.lastname: Martin-Malpartida
authors.forename: Xavier
authors.initials: X
authors.lastname: Verdaguer
authors.forename: Pilar
authors.initials: P
authors.lastname: López-Ruiz
authors.forename: Begoña
authors.initials: B
authors.lastname: Colás
authors.forename: María Alicia
authors.initials: MA
authors.lastname: Cortes
authors.forename: Berta
authors.initials: B
authors.lastname: Ponsati
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Macias
authors.forename: Antoni
authors.initials: A
authors.lastname: Riera
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D013004:Somatostatin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D010649:Phenylalanine; D013004:Somatostatin