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Title: Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine.
Author: Martín-Gago, Pablo
Aragón Altarriba, Eric
Gomez-Caminals, Marc
Fernández-Carneado, Jimena
Ramón, Rosario
Martin-Malpartida, Pau
Verdaguer i Espaulella, Xavier
López-Ruiz, Pilar
Colás, Begoña
Cortes, María Alicia
Ponsati, Berta
Macias, Maria Jesus
Riera i Escalé, Antoni
Keywords: Somatostatina
Hormones peptídiques
Disseny de medicaments
Ressonància magnètica nuclear
Anàlisi conformacional
Peptide hormones
Drug design
Nuclear magnetic resonance
Conformational analysis
Issue Date: 25-Nov-2013
Publisher: MDPI Publishing
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.
Note: Reproducció del document publicat a:
It is part of: Molecules, 2013, vol. 18, num. 12, p. 14564-14584
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ISSN: 1420-3049
Appears in Collections:Articles publicats en revistes (Química Inorgànica i Orgànica)
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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