Design and synthesis of an optimized positional scanning library of peptoids: identification of novel multidrug resistance reversal agents

Masip, Isabel; Cortés, Nuria; Abad, Maria-José; Guardiola, Marisa; Pérez‐Payá, Enrique; Ferragut, José A.; Ferrer‐Montiel, Antonio; Messeguer, Àngel

doi:10.1016/j.bmc.2005.01.024

Cited by 36 publications

(37 citation statements)

References 28 publications

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“…We reasoned that peptidomimetic molecules capable of occupying this pocket with sufficient affinity could compete with Uev1 for its interaction with Ubc13, thereby inhibiting the enzymatic activity of the heterodimer. We used a combinatorial chemical library based on trimers of N-alkylglycines (peptoids) [32], [33] as an initial source of peptidomimetic structures. Peptoids are characterized by a peptide scaffold with side chains attached to the backbone nitrogen atoms [32], which confers them with several structural properties of peptides [34], [35], together with the desirable pharmacological property of being more resistant to proteolytic enzymes [36].…”

Section: Resultsmentioning

confidence: 99%

Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation

et al. 2010

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BackgroundSeveral pathways that control cell survival under stress, namely RNF8-dependent DNA damage recognition and repair, PCNA-dependent DNA damage tolerance and activation of NF-κB by extrinsic signals, are regulated by the tagging of key proteins with lysine 63-based polyubiquitylated chains, catalyzed by the conserved ubiquitin conjugating heterodimeric enzyme Ubc13-Uev.Methodology/Principal FindingsBy applying a selection based on in vivo protein-protein interaction assays of compounds from a combinatorial chemical library followed by virtual screening, we have developed small molecules that efficiently antagonize the Ubc13-Uev1 protein-protein interaction, inhibiting the enzymatic activity of the heterodimer. In mammalian cells, they inhibit lysine 63-type polyubiquitylation of PCNA, inhibit activation of NF-κB by TNF-α and sensitize tumor cells to chemotherapeutic agents. One of these compounds significantly inhibited invasiveness, clonogenicity and tumor growth of prostate cancer cells.Conclusions/SignificanceThis is the first development of pharmacological inhibitors of non-canonical polyubiquitylation that show that these compounds produce selective biological effects with potential therapeutic applications.

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Section: Resultsmentioning

confidence: 99%

Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation

et al. 2010

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“…[20][21][22] We have now modified the diversity of the library to generate an optimised version of the original library in terms of composition and concentration of the different components. 23 The library consists in 52 controlled mixtures and a total of 5120 compounds. The mixtures were screened for their ability to prevent the apoptosome-dependent activation of procaspase-9.…”

Section: Resultsmentioning

confidence: 99%

Small molecule inhibitors of Apaf-1-related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis

et al. 2005

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Apoptosis is a biological process relevant to human disease states that is strongly regulated through protein-protein complex formation. These complexes represent interesting points of chemical intervention for the development of molecules that could modulate cellular apoptosis. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated Apaf-1 (apoptotic proteaseactivating factor), dATP and procaspase-9 that link mitochondria disfunction with activation of the effector caspases and in turn is of interest for the development of apoptotic modulators. In the present study we describe the identification of compounds that inhibit the apoptosome-mediated activation of procaspase-9 from the screening of a diversityoriented chemical library. The active compounds rescued from the library were chemically optimised to obtain molecules that bind to both recombinant and human endogenous Apaf-1 in a cytochrome c-noncompetitive mechanism that inhibits the recruitment of procaspase-9 by the apoptosome. These newly identified Apaf-1 ligands decrease the apoptotic phenotype in mitochondrial-mediated models of cellular apoptosis. Keywords: apoptosis; apoptosome; Apaf-1; caspasa-3; caspasa-9; combinatorial libraries; inhibitor; molecular recognition; peptoid; protein-protein interactions; small molecule Abbreviations: Apaf-1, apoptotic protease-activating factor; DEVDase, hydrolysis of Ac-DEVD-afc; DTT, dithiothreitol; FCS, fetal-calf serum; MEFs, mouse embryo fibroblasts; MMP, mitochondrial membrane potential; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Ni-NTA, (Ni 2 þ -nitrilotriacetate)-agarose; peptoid f1a, 5 0 -6 0 carboxyfluorescein-labelled peptoid 1a; PBS, phosphate-buffered saline; PGA, poly-(L-glutamic acid); rApaf-1, recombinant Apaf-1

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“…As a source of chemical diversity, we used a positional scanning diversity-oriented library of alkylglycines trimers (peptoids) composed of 52 controlled mixtures and a total of 5,120 compounds. 128,159,160 From the four discrete compounds, derived from the library screening and deconvolution (hit rate 0.08%) that inhibited the in vitro apoptosome-dependent activation of procaspase-9, the most potent was peptoid 1 (Table I). Peptoid 1 contains two dichlorophenylethylamino moieties that were found to be important for activity.…”

Section: Synthetic Inhibitors Of the Apaf-1-mediated Apoptosome Assemmentioning

confidence: 99%

Molecules that modulate Apaf‐1 activity

Pérez‐Payá

Orzáez

Mondragón

et al. 2011

Medicinal Research Reviews

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Programmed cell death, apoptosis, is a highly regulated cellular pathway, responsible for the elimination of cells in the organism that are no longer needed or extensively damaged. Defects in the regulation of apoptosis could be at the molecular basis of different diseases, either when it is insufficient or excessive. The formation of the macromolecular complex, apoptosome, is a key event in this pathway, which has also been defined as the intrinsic apoptosis pathway. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated apoptotic protease-activating factor (Apaf-1), dATP, and procaspase-9. Recent studies have produced a wealth of information about the regulation and functions of Apaf-1, but additional studies aimed at elucidating its role as a signaling device at the crosstalk between different signaling pathways are needed to take advantage for the development of modulators of apoptosis pathways and possible therapeutic applications.

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Design and synthesis of an optimized positional scanning library of peptoids: identification of novel multidrug resistance reversal agents

Cited by 36 publications

References 28 publications

Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation

Protein-Protein Interaction Antagonists as Novel Inhibitors of Non-Canonical Polyubiquitylation

Small molecule inhibitors of Apaf-1-related caspase- 3/-9 activation that control mitochondrial-dependent apoptosis

Molecules that modulate Apaf‐1 activity

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