121773-05-5Relevant articles and documents
Allosteric modulation of the dopamine receptor by conformationally constrained type VI β-turn peptidomimetics of Pro-Leu-Gly-NH2
Vartak, Ashish P.,Skoblenick, Kevin,Thomas, Nancy,Mishra, Ram K.,Johnson, Rodney L.
, p. 6725 - 6729 (2008/09/17)
A peptidomimetic of Pro-Leu-Pro-NH2, 7, possessing an indolizidinone type VI β-turn mimic was synthesized via improved high-yielding protocols for the preparation and Cbz protection of α-allylproline. Bicyclic peptidomimetic 7 and spirobicylic
Novel bicyclic lactams as XaaPro type VI β turn mimics: Design, synthesis, and evaluation
Kim, Kyonghee,Dumas, Jean-Philippe,Germanas, Juris P.
, p. 3138 - 3144 (2007/10/03)
The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI β turn is described. The mimics duplicate the conformation of the backbone and disposition of the side-chain atoms of the central two residues of the turn. The Gly L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2'-propenyl)proline. 1H NMR spectroscopy defined the relative stereochemistry of the substituents and conformational characteristics of the six-membered ring of the lactam; X-ray crystallographic analysis confirmed the conformational and stereochemical assignment. Examination of the crystal structure of lactam 6 revealed that the central amide bond was twisted appreciably out of planarity. The twisting of the amide bond was attributed to angle strain resulting from the presence of the sp2-hybridized nitrogen atom at the junction of the two rings. Alkylation of the enolate of the N,N-dimethylformamidine derivative of lactam 6 with benzyl bromide afforded stereoselectively the formamidine 11, a mimic of an L-Phe L-Pro dipeptide in the type VI turn conformation. The efficient synthetic route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide structure-function studies.
Synthesis of a type-VIβ-turn peptide mimetic and its incorporation into a high-affinity somatostatin receptor ligand
Gramberg,Weber,Beeli,Inglis,Bruns,Robinson
, p. 1588 - 1606 (2007/10/02)
The synthesis of a cis-Phe-Pro dipeptide mimetic is described, which adopts a type-VIβ-turn conformation. In this mimetic, the α-positions of Phe and Pro are joined by a CH2CH2 bridge, thereby forming a fused bicyclic system, and fixing a geometry similar to that seen in cis-Phe-Pro units in protein crystal structures. The dipeptide mimetic 20 was synthesized in optically pure form starting from (R)-α-allylproline, with a free carboxylic acid and an Fmoc-protected N-terminus, thereby allowing its incorporation into linear and cyclic peptides using standard solid-phase methods. The mimetic 20 was incorporated into the cyclic somatostatin analogue cyclo(-Phe = Pro-Phe-D-Trp-Lys-Thr-), where Phe = Pro represents the mimetic. This analogue shows a high affinity (pIC50 8.6) for somatostatin receptors on rat-brain cortex membranes. Based on NMR studies in aqueous solution, likely low-energy conformations for this analogue were deduced using restrained dynamic simulated annealing. The conformations found, which include a distorted type-II' turn at D-Trp-Lys, are similar to low-energy conformations deduced elsewhere for cyclo(-Phe-Pro-Phe-D-Trp-Lys-Thr-), as well as to those seen in crystal structures of the somatostatin analogue octreotide.
Design and synthesis of a cis-Gly-Pro, type-VI turn, dipeptide mimetic and its use in Fmoc-solid phase peptide synthesis
Gramberg,Robinson
, p. 861 - 864 (2007/10/02)
The Fmoc-protected bicyclic molecules 7 and 8 have been produced as cis-Gly-Pro peptide mimetics in nine synthetic steps starting from optically pure (R)-2-allylproline. Their use in solid-phase peptide synthesis has been demonstrated by their incorporati
DESIGN, SYNTHESIS AND EVALUATION OF A NOVEL BICYCLIC LACTAM AS A GLY-PRO TYPE VI BETA-TURN MIMIC
Dumas, Jean-Philippe,Germanas, Juris Paul
, p. 1493 - 1496 (2007/10/02)
The stereoselective synthesis and conformational evaluation of Gly-Pro type VI turn mimic 7, the first mimetic to constrain the central three bonds and incorporate the side chain groups of a beta-turn, is described.A superimposition of the crystallographi
Synthesis, conformational, properties, and antibody recognition of peptides containing β-turn mimetics based on α-alkylproline derivates
Hinds,Welsh,Brennand,Fisher,Glennie,Richards,Turner,Robinson
, p. 1777 - 1789 (2007/10/02)
Peptide recognition by monoclonal antibodies may provide a useful model for drug development, in particular to test the effects of conformational restriction on ligand binding. We have tested the influence of novel peptide mimetics upon conformation and binding affinity for the case of monoclonal antibodies raised to a peptide antigen which displays a preference for a β-turn conformation in aqueous solution. Two monoclonals were isolated that recognized the peptide Ac-Tyr-Pro-Tyr-Asp-Val-Pro-Asp-Tyr-Ala specifically at the β-turn formed by Tyr-Pro-Tyr-Asp. Peptide analogues were then synthesized containing mimetics designed to stabilize this conformation. One, analogue (3), contained a spirocyclic γ-lactam bridge between the α-position of proline-2 and the N atom of tyrosine-3, while another (2) contained (S)-α-methylproline at position 2. NMR spectroscopy and molecular modeling suggest that both analogues adopt reverse-turn conformations stablized relative to that in the native sequence. For the (S)-α-methylproline analogue binding to both monoclonal antibodies was substantially improved, compared with the native antigen, whereas the γ-lactam analogue (3) was not recognized by either antibody. Quantitative equilibrium ultrafiltration binding assays showed that the affinities of the (S)-α-methylproline analogue (2) for the two antibodies were improved over those measured with the native antigen by -2.3 and -0.65 kcal/mol. The origins of these free energy differences cannot be explained wholly on the basis of presumed extra hydrophobic contacts between the new methyl substituent and the antigen binding sites. We propose that the increased conformational stability of the analogue plays a decisive role, implying that the reverse turn detected in the native antigen, possibly a type-I turn, is important for recognition by the two antibodies.
Design and Synthesis of a Novel Peptide β-Turn Mimetic
Hinds, Mark G.,Richards, Nigel G.J.,Robinson, John A.
, p. 1447 - 1449 (2007/10/02)
The stereospecific synthesis of the novel spirocyclic unit (7), and its use in the construction by solid phase methods, of a conformationally locked analogue of the immunodominant nonapeptide (1) is described.
