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Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine
Institute for Research in Biomedicine (IRB Barcelona) Baldiri Reixac, 10, Barcelona 08028, Spain
BCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars, Sector II. Ctra. Comarcal 244, Km. 22, 08777 Sant Quintí de Mediona, Barcelona 08777, Spain
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués, 1-11, Barcelona 08028, Spain
Departamento de Bioquímica y Biología Molecular, Universidad de Alcalá de Henares, Facultad de Medicina, Madrid 28871, Spain
Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluis Companys, 23, Barcelona 08010, Spain
* Authors to whom correspondence should be addressed.
Received: 30 October 2013; in revised form: 12 November 2013 / Accepted: 13 November 2013 / Published: 25 November 2013
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
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MDPI and ACS Style
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.
Martín-Gago P, Aragón E, Gomez-Caminals M, Fernández-Carneado J, Ramón R, Martin-Malpartida P, Verdaguer X, López-Ruiz P, Colás B, Cortes MA, Ponsati B, Macias MJ, Riera A. Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine. Molecules. 2013; 18(12):14564-14584.
Martín-Gago, Pablo; Aragón, Eric; Gomez-Caminals, Marc; Fernández-Carneado, Jimena; Ramón, Rosario; Martin-Malpartida, Pau; Verdaguer, Xavier; López-Ruiz, Pilar; Colás, Begoña; Cortes, María A.; Ponsati, Berta; Macias, Maria J.; Riera, Antoni. 2013. "Insights into Structure-Activity Relationships of Somatostatin Analogs Containing Mesitylalanine." Molecules 18, no. 12: 14564-14584.