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Molecules 2013, 18(12), 14564-14584; doi:10.3390/molecules181214564
Article

Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine

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Received: 30 October 2013 / Revised: 12 November 2013 / Accepted: 13 November 2013 / Published: 25 November 2013
(This article belongs to the Section Medicinal Chemistry)
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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.
Keywords: somatostatin; drug design; peptidic hormones; non-covalent interactions; NMR; structure-activity relationships; conformational analysis somatostatin; drug design; peptidic hormones; non-covalent interactions; NMR; structure-activity relationships; conformational analysis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Martín-Gago, P.; Aragón, E.; Gomez-Caminals, M.; Fernández-Carneado, J.; Ramón, R.; Martin-Malpartida, P.; Verdaguer, X.; López-Ruiz, P.; Colás, B.; Cortes, M.A.; Ponsati, B.; Macias, M.J.; Riera, A. Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine. Molecules 2013, 18, 14564-14584.

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