Peptide aromatic interactions modulated by fluorinated residues: Synthesis, structure and biological activity of Somatostatin analogs containing 3-(3',5'difluorophenyl)-alanine.
Somatostatin is a 14-residue peptide hormone that regulates the endocrine system by binding to five G-protein-coupled receptors (SSTR1-5). We have designed six new Somatostatin analogs with L-3-(3',5'-difluorophenyl)-alanine (Dfp) as a substitute of Phe and studied the effect of an electron-poor aromatic ring in the network of aromatic interactions present in Somatostatin. Replacement of each of the Phe residues (positions 6, 7 and 11) by Dfp and use of a D-Trp8 yielded peptides whose main conformations could be characterized in aqueous solution by NMR. Receptor binding studies revealed that the analog with Dfp at position 7 displayed a remarkable affinity to SSTR2 and SSTR3. Analogs with Dfp at positions 6 or 11 displayed a π-π interaction with the Phe present at 11 or 6, respectively. Interestingly, these analogs, particularly [D-Trp8,L-Dfp11]-SRIF, showed high selectivity towards SSTR2, with a higher value than that of Octreotide and a similar one to that of native Somatostatin.
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.
Pablo
P
Martín-Gago
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.
Álvaro
Á
Rol
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.
Toni
T
Todorovski
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.
Eric
E
Aragón
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.
Pau
P
Martin-Malpartida
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.|Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués, 1-11, Barcelona 08028, Spain.
Xavier
X
Verdaguer
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.
Mariona
M
Vallès Miret
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.
Jimena
J
Fernández-Carneado
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.
Berta
B
Ponsati
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys, 23, Barcelona 08010, Spain.
Maria J
MJ
Macias
Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, Barcelona 08028, Spain.|Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués, 1-11, Barcelona 08028, Spain.
Antoni
A
Riera
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D054879:Halogenation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship
D010456:Peptides, Cyclic; D013004:Somatostatin; D000409:Alanine