Conformationally constrained biologically active peptides: tentative identification of the antimitogenic bioactive confomer of the naturally occurring cyclic tetrapeptides

Shute, Richard E.; Kawai, Megumi; Rich, Daniel H.

doi:10.1016/s0040-4020(01)86109-3

Cited by 39 publications

(23 citation statements)

References 45 publications

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“…These α-epoxyketones were proposed to function as irreversible inhibitors of histone deacetylase by crosslinking with active site nucleophiles at low concentrations [105][106][107]141]. In contrast, trichostatin A (3) which lacked this electrophilic component, was a noncompetitive inhibitor of HDAC exhibiting reversible enzyme inhibition while possessing a biological profile reminiscent of these cyclotetrapeptides.…”

Section: Structure-activity Relationship In the Cyclopeptide Seriesmentioning

confidence: 99%

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Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Meinke¹,

Liberator²

2001

CMC

108

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Histone deacetylase (HDAC) and histone acetyltransferase (HAT) are enzymes that influence transcription by selectively deacetylating or acetylating the eta-amino groups of lysines located near the amino termini of core histone proteins. It is well-established that in transcriptionally active chromatin, histones generally are hyperacetylated and, conversely, hypoacetylated histones are coincident with silenced chromatin. Revived interest in these enzymatic pathways and how they modulate eukaryotic transcription has led to the identification of multiple cofactors whose complex interplay with HDAC affects gene expression. Concurrent with these discoveries, screening of natural product sources yielded new small molecules that were subsequently identified as potent inhibitors of HDAC. While predominantly identified using antiproliferative assays, the biological activity of these new HDAC inhibitors also encompasses significant antiprotozoal, antifungal, phytotoxic and antiviral applications. These newly discovered HDAC inhibitors served as lead structures for the development of improved derivatives including related reagents with considerable potential as tools to further elucidate the mechanism of transcriptional regulation.

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Section: Structure-activity Relationship In the Cyclopeptide Seriesmentioning

confidence: 99%

“…Inverting the stereochemistry of chlamydocin's epoxide also attenuated potency. Incidentally, the tetrapeptide core also was integral for useful biological activity as N-Ac-D,L-Aoe-OEt was inactive [141].…”

Section: Structure-activity Relationship In the Cyclopeptide Seriesmentioning

confidence: 99%

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Meinke¹,

Liberator²

2001

CMC

108

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“…Two important challenges in studying cyclic tetrapeptides as drugs are the often poor synthetic efficiency in constructing the strained 12-membered ring and the inability to control cis – trans backbone isomerization, which leads to multiple backbone conformations in solution 12,22,23. These difficulties have provoked several previous strategies involving modification of the cyclic tetrapeptide backbone to facilitate their synthesis and reduce their conformational heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Biological Evaluation, and Structural Characterization of Potent Histone Deacetylase Inhibitors Based on Cyclic α/β-Tetrapeptide Architectures

et al. 2009

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Histone deacetylases (HDACs) are a family of enzymes found in bacteria, fungi, plants, and animals that profoundly affect cellular function by catalyzing the removal of acetyl groups from ε-Nacetylated lysine residues of various protein substrates including histones, transcription factors, α-tubulin, and nuclear importers. Although the precise roles of HDAC isoforms in cellular function are not yet completely understood, inhibition of HDAC activity has emerged as a promising approach for reversing the aberrant epigenetic states associated with cancer and other chronic diseases. Potent new isoform selective HDAC inhibitors would therefore help expand our understanding of the HDAC enzymes and would represent attractive lead compounds for drug design, especially if combined with high resolution structural analyses of such inhibitors to shed light on the three-dimensional pharmacophoric features necessary for the future design of more potent and selective compounds. Here we present structural and functional analyses of a series of β-amino acid-containing HDAC inhibitors inspired by cyclic tetrapeptide natural products. To survey a diverse ensemble of pharmacophoric configurations, we systematically varied the position of the β-amino acid, amino acid chirality, functionalization of the Zn 2+ -coordinating amino acid side chain, and alkylation of the backbone amide nitrogen atoms around the macrocycle. In many cases, the compounds were a single conformation in solution and exhibited potent activities against a number of HDAC isoforms as well as effective antiproliferative and cytotoxic activities against human tumor cells. High resolution NMR solution structures were determined for a selection of the inhibitors, providing a useful means of correlating detailed structural information with potency. The structure-based approach described here is expected to furnish valuable insights toward the future design of more selective HDAC inhibitors.

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“…Finally, a crystallographic structure obtained from CHCl 3 /methanol/pentane contained a cis -amide at the Pip residue. [3] The observation of both cis- and trans -tertiary amides in these structures of apicidin (as well as other members of the tetrapeptide natural product family[8,12]), combined with the lack of any co-crystal structure of a cyclic tetrapeptide inhibitor with an HDAC enzyme, led us to question which amide configuration is present in the dominant bioactive conformation. Although the c - t - t - t conformation had previously been tentatively identified as the bioactive structure in related cyclic tetrapeptides based on a correlation of activity with predicted or known solution conformations,[12] we aimed to carry out a more controlled study in which apicidin analogs having either a fixed cis- or trans -amide isostere could be directly compared in an HDAC inhibition assay.…”

mentioning

confidence: 99%

“…On the other hand, peptide 12 contained a cis configuration at the Aoda–Trp amide, leading to a cis – trans – cis – trans ( c - t - c - t ) tetrapeptide conformation (Figures 2c, S3). The c - t - c - t structure has been the focus of several calculations and discussions in the literature,[12,22,23] likely because it is among the most common conformations observed in the structures of cyclic tetrapeptides and is reportedly the conformation having the least ring strain. 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 .…”

mentioning

confidence: 99%

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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Conformationally constrained biologically active peptides: tentative identification of the antimitogenic bioactive confomer of the naturally occurring cyclic tetrapeptides

Cited by 39 publications

References 45 publications

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Histone Deacetylase: A Target for Antiproliferative and Antiprotozoal Agents

Design, Synthesis, Biological Evaluation, and Structural Characterization of Potent Histone Deacetylase Inhibitors Based on Cyclic α/β-Tetrapeptide Architectures

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

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