Development of a new family of conformationally restricted peptides as potent nucleators of beta-turns. Design, synthesis, structure, and biological evaluation of a beta-lactam peptide analogue of melanostatin.
Novel enantiopure (i)-(beta-lactam)-(Gly)-(i+3) peptide models, defined by the presence of a central alpha-alkyl-alpha-amino-beta-lactam ring placed as the (i+1) residue, have been synthesized in a totally stereocontrolled way by alpha-alkylation of suitable N-[bis(trimethylsilyl)methyl]-beta-lactams. The structural properties of these beta-lactam pseudopeptides have been studied by X-ray crystallography, Molecular Dynamics simulation, and NOESY-restrained NMR simulated annealing techniques, showing a strong tendency to form stable type II or type II' beta-turns either in the solid state or in highly coordinating DMSO solutions. Tetrapeptide models containing syn- or anti-alpha,beta-dialkyl-alpha-amino-beta-lactam rings have also been synthesized and their conformations analyzed, revealing that alpha-alkyl substitution is essential for beta-turn stabilization. A beta-lactam analogue of melanostatin (PLG amide) has also been prepared, characterized as a type-II beta-turn in DMSO-d6 solution, and tested by competitive binding assay as a dopaminergic D2 modulator in rat neuron cultured cells, displaying moderate agonist activity in the micromolar concentration range. On the basis of these results, a novel peptidomimetic design concept, based on the separation of constraint and recognition elements, is proposed.
Palomo
Claudio
C
Departamento de Química Orgánica I. Facultad de Química, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastián, Spain. qoppanic@sc.ehu.es
Aizpurua
Jesus M
JM
Benito
Ana
A
Miranda
José Ignacio
JI
Fratila
Raluca M
RM
Matute
Carlos
C
Domercq
Maria
M
Gago
Federico
F
Martin-Santamaria
Sonsoles
S
Linden
Anthony
A
D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013237:Stereoisomerism; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D009842:Oligopeptides; D017448:Receptors, Dopamine D2; D047090:beta-Lactams; D009075:MSH Release-Inhibiting Hormone