Conformational analysis of an active chemotactic peptide analog containing z-dehydrophbnylalanine at position 3

Recently, a novel chiral intermolecular interaction was found in an N-deprotected achiral nonapeptide that undergoes the predominance of one-handed screw sense through the addition of chiral small carboxylic acid (Inai, Y.; Tagawa, K.; Takasu, A.; Hirabayashi, T.; Oshikawa, T.; Yamashita, M. J. Am. Chem. Soc. 2000, 122, 11731). We here clarify to what extent such noncovalent chiral domino effect affects the helical screw sense of an N-deprotected chiral peptide. Two chiral peptides consisting of C-terminal L-Leu (1) or L-Leu(2) (2) and the preceding achiral helical octapeptide segment were employed. NMR and IR spectroscopy, and energy calculation indicated that both peptides adopt a helical conformation in chloroform. Peptide 1 showed a small excess of a left-handed screw sense for the achiral helical octapeptide, but peptide 2 strongly preferred a right-handed screw sense. The addition of chiral Boc amino acid to a chloroform solution of peptide 1, depending on its chirality, underwent a unique helix-to-helix transition or led to remarkable stabilization of the original left-handed screw sense. Peptide 2 retained the original right-handed screw sense on addition of chiral Boc-amino acid, but its helical stability changed to some extent depending on its added chirality. Therefore, the importance of noncovalent domino effect for controlling the helical screw sense or helical stability of a chiral peptide has been demonstrated here for the first time. In addition, we here have presented a unique system that both N-terminal noncovalent and C-terminal covalent domino effects operate simultaneously on the helical screw sense of a single achiral segment and have compared both powers for inducing the screw sense bias.

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“…Boc-Aib- Δ Z Phe-OMe. The dipeptide was prepared by ring-opening reaction of Boc-Aib-Δ Z Phe azlactone 5 with methanol . Yield 98%.…”

Section: Methodsmentioning

confidence: 99%

Noncovalent Domino Effect on Helical Screw Sense of Chiral Peptides Possessing C-Terminal Chiral Residue

et al. 2002

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“…To probe the structural requirement, these groups were mutated with residues having different steric, charge, and hydrophobic groups, and constraints were introduced to achieve the desired conformation. A large number of analogs of fMLP have been designed and synthesized, examined for their biological activities, and quite a few have also been studied for their conformation using X‐ray crystallography and NMR techniques 2, 9–22, 52–95. Results of conformational and activity studies on these peptides are summarized in Table V.…”

Section: Discussionmentioning

confidence: 99%

Conformational investigations on analogs of inflammation response inducing chemotactic tripeptide fMLP

Rathore

2005

Biopolymers

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Conformations of three analogs of for-L-Met-L-Leu-L-Phe-OH (fMLP), which initiates inflammatory response by interaction with the formyl peptide receptor (FPR), have been investigated by the application of the X-ray crystallographic technique. The investigated analogs of fMLP peptides are as follows: for-L-Met-1-amino-1-cyclooctane-carbonyl(Ac8c)-L-Phe-OMe; for-L-Met-L-Leu-L-p-iodo-Phe-OH; and for-L-Met-di-n-propylglycyl(Dpg)-L-Phe-OMe. The peptide backbone in and is constrained at position of fMLP by the introduction of Calpha,alpha-disubstituted glycines. In peptide, Phe-OMe is substituted by p-iodo-Phe-OH. Crystal structures reveal an overall folded conformation adopted by and. The former is folded in the type II beta-turn, which is stabilized by an intramolecular 1<--4 (formyl) C==O...H--N (Phe) hydrogen bond, whereas the latter is folded in an open turn without any intramolecular hydrogen bond. On the other hand, peptide has an extended conformation, and two different molecules in a crystallographic asymmetric unit form an antiparallel beta-sheet-like structure. In and, residues Ac8c and Dpg adopt left-handed helical and fully extended (C5) conformations, respectively. The cyclooctane ring in Ac8c acquires a boat-chair conformation. Crystal packing of is characterized by the association of aliphatic-aromatic rings via a C--H...pi interaction. In the crystal of, contrary to the usual observations, peptides are interlinked via networks of head-to-tail hydrogen bond and pi...pi interactions, which are generally observed to be mutually exclusive. The structure-function mechanism of the ligand-receptor interaction is discussed.

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Cyclic Analogs of Chemotactic Formylpeptides, I.: Synthesis and Biological Activity of For‐Cys‐Leu‐Phe‐Cys‐OMe

Zecchini¹,

Paradisi²,

Torrini³

et al. 1993

Archiv der Pharmazie

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By using the side chain to side chain mode of cyclization the 14-membered disulfide cyclopeptide For-Cis-Leu-Phe-Cys-OMe ( 5 ) has been synthesized as conformationally constrained analog of the prototypical chemotactic tripeptide For-Met-Leu-Phe-OMe. Compound 5 is inactive towards human neutrophils. The lack of biological activity of cyclotetrapeptide 5 is discussed taking into account the backbone folding and the side chain topography.Continuous efforts are being devoted to clarify the conformation-activity relationships in the field of chemotactic N-formylmethionyl peptides. Much results derive from a systematic alteration of the backbone conformational preferences performed on For-Met-Leu-Phe-OH (fMLP), the prototypical ligand of formylpeptide receptors. The adopted strategy consists in the replacement of native a-amino acids with suitable a,a-disubstituted'-i), a,P-unsat~rated~.~) and related conformationally constrained resi-dues6), in order to induce specific backbone conformations into the parent linear tripeptide.An analysis of the literature reveals that the complementary approach, based on the introduction of conformational restriction through medium and long-range backbone cyclizationnamely cyclization between residue i and i + n (with n > 1)7) -has not been examined. Thus, as a prosecution of our efforts to elucidate the conformational requirements of formylpeptide receptors, we are now examining a series of cyclic peptide analogs of fMLP-OMe and here report data concerning the first model, namely the cyclotetrapeptide 5. 5 This compound has been obtained by using the side chain to side chain mode of cyclization, an approach which allows the maintenance of the formylated N-terminal amino group, which is critical for the bioactivity, as well as the C-Cyclische Analoga chemotaktischer Formylpeptide, 1. Mitt.: Synthese und biologische Aktivitat von For-Cys-Leu-Phe-Cys-OMe Durch Cyclisierung von Seitenkette zu Seitenkette wurde das 14-gliedrige Disulfid-Cyclopeptid For-Cys-Leu-Phe-Cys-OMe ( 5 ) als Analogon des chemotaktischen Tripeptides For-Met-Leu-Phe-OMe mit eingeschrankter konformativer Beweglichkeit hergestellt. 5 ist gegeniiber menschlichen Neutrophilen inaktiv. Der Mange1 an biologischer Aktivitat des Cyclotetrapeptides 5 wird unter den Gesichtspunkten der Faltung des Peptides und der Seitenketten-Topographie diskutiert.terminal carboxymethyl group. Compound 5 shares with the parent tripeptide the presence of the lipophilic side chains of leucine and phenylalanine at the second and third position respectively and contains a fourth amino acid residue at the C-terminal position. This latter feature appears of interest since both early8) and recent') observations clearly indicate the positive effect on the bioactivity of the incorporation of a fourth amino acid residue at the C-terminal position of the chemotactic tripeptide fMLP.Although 5 lacks the N-terminal methionine side chain ( Fig. 1,a) which is important for the receptor recognition, it maintains both the &sulfur and the &-carbon atom ( F...

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Conformational analysis of an active chemotactic peptide analog containing z-dehydrophbnylalanine at position 3

Cited by 15 publications

References 20 publications

Noncovalent Domino Effect on Helical Screw Sense of Chiral Peptides Possessing C-Terminal Chiral Residue

Noncovalent Domino Effect on Helical Screw Sense of Chiral Peptides Possessing C-Terminal Chiral Residue

Conformational investigations on analogs of inflammation response inducing chemotactic tripeptide fMLP

Cyclic Analogs of Chemotactic Formylpeptides, I.: Synthesis and Biological Activity of For‐Cys‐Leu‐Phe‐Cys‐OMe

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