Direct design of a potent non-peptide fibrinogen receptor antagonist based on the structure and conformation of a highly constrained cyclic RGD peptide

Ku, Thomas W.; Ali, Fadia E.; Barton, Linda S.; Bean, James C.; Bondinell, William E.; Burgess, Joelle L.; Callahan, James F.; Calvo, Raul R.; Chen, Lichong

doi:10.1021/ja00072a058

Cited by 97 publications

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“…fibronectin, vitronectin and fibrinogen) adhesion. In addition, RGD peptides can inhibit platelet aggregation mediated by the platelet receptor GP IIb/IIIa with fibrinogen (1, 2). Therefore, RGD peptides and peptidomimetics have been investigated as potential antithrombic agents (3).…”

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confidence: 99%

The effect of conformation on the solution stability of linear vs. cyclic RGD peptides

Bogdanowich-Knipp

Jois

Siahaan

1999

The Journal of Peptide Research

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The objective of this study was to evaluate the relationship between conformational flexibility and solution stability of a linear RGD peptide (Arg-Gly-Asp-Phe-OH; 1) and a cyclic RGD peptide (cyclo-(1, 6)-Ac-Cys-Arg-Gly-Asp-Phe-Pen-NH2; 2); as a function of pH. Previously, it was found that cyclic peptide 2 was 30-fold more stable than linear peptide 1. Therefore, this study was performed to explain the increase in chemical stability based on the preferred conformation of the peptides. Molecular dynamics simulations and energy minimizations were conducted to evaluate the backbone flexibility of both peptides under simulated pH conditions of 3, 7 and 10 in the presence of water. The reactive sites for degradation for both molecules were also followed during the simulations. The backbone of linear peptide 1 exhibited more flexibility than that of cyclic peptide 2, which was reflected in the rotation about the phi and psi dihedral angles. This was further supported by the low r.m.s. deviations of the backbone atoms for peptide 2 compared with those of peptide 1 that were observed among structures sampled during the molecular dynamics simulations. The presence of a salt bridge between the side chain groups of the Arg and Asp residues was also indicated for the cyclic peptide under simulated conditions of neutral pH. The increase in stability of the cyclic peptide 2 compared with the linear peptide 1, especially at neutral pH, is due to decreased structural flexibility imposed by the ring, as well as salt bridge formation between the side chains of the Arg and Asp residues in cyclic peptide 2. This rigidity would prevent the Asp side chain carboxylic acid from orienting itself in the appropriate position for attack on the peptide backbone.

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confidence: 99%

The effect of conformation on the solution stability of linear vs. cyclic RGD peptides

Bogdanowich-Knipp

Jois

Siahaan

1999

The Journal of Peptide Research

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“…Eight compounds turned out to be weak or inactive ligands (6,7,9,15,30,33,36,37). The conformations of most of the compounds have been conÐrmed by X-ray structure determination (1, 9È11, 16,19,21,23,28,29,35), NMR spectroscopy (3È6, 12, 13, 17, 20, 22, 26, 27, 30È32, 34, 36) or modelling studies (7,8,14,24,33,37). Surprisingly, to the best of our knowledge, there is only one example (compound 28) where the predicted and the experimentally determined structure of the protein (thrombin) in complex with the ligand was published.28 The importance of peptidomimetics for peptide research is not questioned.…”

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confidence: 99%

Extended Summaries: Turn mimetics for peptide design

Egner¹,

Müller‐Fahrnow²,

Eckle³

1997

Pestic. Sci.

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“…After initial attempts with 2-azepinones [70], extensive investigations on differently substituted 1,4-benzodiazepine non-peptide analogues were carried out. Several potent peptidomimetics were discovered, as exemplified here by the orally active α IIb β 3 antagonist 13 [71,72]. A similar approach led to the identification of non-peptide α V β 3 antagonists, such as 14, revealing the versatility of the benzodiazepine nucleus as a Gly-Asp mimetic [73,74].…”

Section: β-Turn-based Peptidomimetics As Antagonists Of Integrinsmentioning

confidence: 99%

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

Vega

Martı́n-Martı́nez²,

González‐Muñiz

2007

CTMC

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In view of the crucial role of protein-protein intercommunication both in biological and pathological processes, the search of modulators of protein-protein interactions (PPIs) is currently a challenging issue. The development of rational strategies to imitate key secondary structure elements of protein interfaces is complementary to other approaches based on the screening of synthetic or virtual libraries. In this sense, the present review provides representative examples of compounds that are able to disturb PPIs of therapeutic relevance, through the stabilization or the imitation of peptide hot-spots detected in contact areas of the interacting proteins. The review is divided into three sections, covering mimetics of the three main secondary structural elements found in proteins, in general, and in protein-protein interfaces, in particular (alpha-helices, beta-sheets, and reverse turns). Once the secondary element has been identified, the first approach typically involves the translation of the primary peptide structure into different cyclic analogues. This is normally followed by gradual decrease of the peptide nature through combination of peptide and non-peptide fragments in the same molecule. The final step usually consists in the development of pertinent organic scaffolds for appending key functional groups in the right spatial disposition, as a means towards totally non-peptide small molecule PPI modulators.

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Direct design of a potent non-peptide fibrinogen receptor antagonist based on the structure and conformation of a highly constrained cyclic RGD peptide

Cited by 97 publications

References 0 publications

The effect of conformation on the solution stability of linear vs. cyclic RGD peptides

The effect of conformation on the solution stability of linear vs. cyclic RGD peptides

Extended Summaries: Turn mimetics for peptide design

Modulation of Protein-Protein Interactions by Stabilizing/Mimicking Protein Secondary Structure Elements

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