Nouveaux cyclotétrapeptides isolés de l'ascidie cystodytes delle chiajei.

Aracil, Jean-Marie; Badre, Ayoub; Fadli, Mohamed; Jeanty, G.; Banaigs, Bernard; Francisco, Christian; Lafargue, F.; Heitz, Annie; Aumelas, André

doi:10.1016/s0040-4039(00)78797-1

Cited by 35 publications

(30 citation statements)

References 7 publications

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“…Although our data indicate that the c - t - c - t conformation is poorly suited to exert potent HDAC inhibitory activity, peptide 12 could be useful as a lead compound in constructing conformationally restricted analogs of other cyclic tetrapeptide natural products that are known to adopt the c - t - c - t conformation, such as tentoxin[23] and dihydrotentoxin[24] or the symmetric natural products cyclo(L-Pro-L-Leu) 2 , cyclo(L-Pro-L-Val) 2 , or cyclo(L-Pro-L-Phe) 2 . [25] Indeed, peptide 12 overlayed closely on the crystal structure of dihydrotentoxin[24] (0.24 Å r.m.s.d. for C α and C β atoms) (Figures 2c, S3).…”

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confidence: 92%

Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic Tetrapeptides

et al. 2009

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Keywords drug design; cyclic peptides; histone deacetylase; structure-activity relationship; triazole A fundamental strategy in rationally designing synthetic compounds to bind a protein of interest is to use a known ligand as a structural model to specify the precise conformational and pharmacophoric requirements for binding. Despite the remarkable success of this approach, a significant difficulty is that free ligands (in the absence of their cognate receptors) often adopt multiple conformations in solution or in the solid state compared to the receptor-bound structure.[1] These occurrences can render design models based on the free ligand structure difficult to obtain or even misleading.[2] Here we present evidence that the more potent conformation of apicidin, an archetypal member of a family of naturally occurring cyclic tetrapeptide inhibitors of histone deacetylases (HDACs), is not the all-trans (t-t-t-t) structure that predominates in solution, [3,4] but rather a cis-trans-trans-trans (c-t-t-t) conformation. Our studies rely on the design, synthesis, structural characterization, and functional analysis of a series of cyclic pseudo-tetrapeptides bearing 1,4-or 1,5-disubstituted 1,2,3-triazole amino acids that serve as trans-or cis-amide bond surrogates, respectively. We show that by replacing an amide bond with a triazole, the bond in question can be fixed in either a trans-like or cis-like configuration, allowing us to individually probe the binding affinity of distinct conformations. The heterocyclic compounds adopt conformations that overlay closely with the targeted conformations of apicidin and demonstrate potent HDAC inhibitory activities, in some cases equivalent or superior to those of the natural product. This study highlights the utility of triazole-modified cyclic peptides in constructing useful

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confidence: 92%

Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic Tetrapeptides

et al. 2009

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“…17 All these peptides present cytotoxic or cytostatic activities and possess one D-amino acid and three L-amino acids, including L-Aoe or L-Aod. In this tentative classification, a last group of cyclopeptides can be distinguished, including fenestin A (10), 18 cyclo(L-Pro-LVal) 2 (11), 19 cyclo(L-Pro-L-Leu) 2 (12), cyclo(L-Pro-L-Phe) 2 (13), and cyclo(L-Pro-L-Tyr-L-Pro-L-Val) (14), 20 all characterized by four L-amino acids, and exhibiting cytotoxic activities as well.…”

Section: Introductionmentioning

confidence: 99%

Predicting the conformational states of cyclic tetrapeptides

et al. 2003

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Biologically active cyclic tetrapeptides, usually found among fungi metabolites, exhibit phytotoxic or cytostatic activities that are likely to be governed by specific conformations adopted in solution. For conformational studies and drug design, there is a strong interest in using fast and reliable methods to determine correctly the conformational population of cyclotetrapeptides. We show here that standard molecular mechanics computational approach gives satisfactory results. The method was validated step by step by experimental data either obtained after synthesis and NMR analysis, or found in the literature. The cyclo(Gly)(4), cyclo(Ala)(4), cyclo(Sar)(4), and cyclo(SarGly)(2) peptides were used to evaluate the prediction of the peptide backbone conformation, and the detailed conformational analysis of tentoxin, a natural phytotoxic cyclotetrapeptide in which N-alkylated peptide bonds alternate with regular secondary ones, was used to validate the computation of conformers proportions. From the knowledge of an initial cyclic primary structure and of the D or L configuration of the amino acids, we show that it is possible to determine the exact orientation of carbonyl groups and to predict the nature of conformers present in solution. The proportion of each conformer can be inferred from a statistical thermodynamics approach by using the potential energy values of each conformer, computed by molecular mechanics methods with the TRIPOS force field, which allowed us to account for the solvent. The solvent contribution was processed by two different methods according to the nature of the interactions: whether through the dielectric constant introduced in the electrostatic potential, when interaction with solute molecules are weak or negligible, or through the computation of free energy of solvation using the algorithm SILVERWARE for solvents explicitly interacting with the solute. When applied to tentoxin, this conformational analysis yielded results in very good agreement with the experimental data reported by Pinet et al. (Biopolymers, 1995, Vol. 36, pp. 135-152), on both the nature of existing conformers and their relative proportions, whatever the nature of the considered solvent.

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“…No activity was reported for Fenestin A. Vinaceuline (41) was isolated as a new cyclotetrapeptide from endophytic Streptomyces sp., along with three known cyclotetrapeptides [66]. Very rare examples of novel cyclotetrapeptides are tataricins A (42) and B (43), which were obtained from the traditional Chinese medicine Aster tataricus [67]. Two other cyclotetrapeptides designated as cyclo-(L-Val-L-Leu-L-Val- Nobilamide D Molluscassociated bacterium -…”

Section: Fig 4 Cyclotetrapeptides Interacting With Metal Ionsmentioning

confidence: 99%

“…18 (L-Pro-L-Val), and cyclo-(L-Pro-L-Phe) 2 have been isolated from a marine ascidian Cystodytes dellechiajei as cytotoxic compounds against L1210 cells [43]. Halolitoralins C (21) and B (22) were isolated from the fermentation broth of a marine sediment derived from Halobacillus litoralis yyYS3106 and exhibited moderate antifungal activity in both human fungi as well as cropthreatening fungi.…”

Section: Introductionmentioning

confidence: 99%

Medicinal significance of naturally occurring cyclotetrapeptides

Abdalla

2016

J Nat Med

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Bioactive natural products are serendipitous drug candidates, which stimulate synthetic approaches for improving and supporting drug discovery and development. Therefore, the search for bioactive metabolites from different natural sources continues to play an important role in fashioning new medicinal agents. Several cyclic peptides were produced by organisms, such as b-defensins, gramicidin S, and tyrocidine A, and exhibited a wide range of bioactivities, such as antiviral activity against HIV-1, influenza A viruses, or antibacterial activity. Cyclic tetrapeptides are a class of natural products that were found to have a broad range of biological activities, promising pharmacokinetic properties, as well as interesting conformational dynamics and ability of slow inter-conversion to several different structures. Cyclooligopeptides, particularly medium ring-sized peptides, were obtained from marine microorganisms and exhibited a wide range of pharmacological properties, including antimicrobial and anti-dinoflagellate activities, cytotoxicity, and inhibitory activity against enzyme sortase B. Most of the naturally occurring cyclotetrapeptides are obtained from fungi. Some natural cyclic tetrapeptides were found to inhibit histone deacetylase (HDAC), which regulate the expression of genes. These compounds are very useful as cancer therapeutics. Various analogues of the natural cyclotetrapeptides were successfully synthesized to find novel lead compounds for pharmacological and biotechnological applications. Therefore, in this review, previously reported novel natural cyclotetrapeptides are briefly discussed, along with their important biological activities as drug candidates, together with their promising therapeutic properties. Moreover, their future perspective in drug discovery as potential therapeutic agents will be determined.

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Nouveaux cyclotétrapeptides isolés de l'ascidie cystodytes delle chiajei.

Cited by 35 publications

References 7 publications

Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic Tetrapeptides

Probing the Bioactive Conformation of an Archetypal Natural Product HDAC Inhibitor with Conformationally Homogeneous Triazole‐Modified Cyclic Tetrapeptides

Predicting the conformational states of cyclic tetrapeptides

Medicinal significance of naturally occurring cyclotetrapeptides

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