RESUMEN

A study on submonomer solid-phase synthesis of S-glycopeptoids has been carried out by screening different parameters. Dimeric species, featuring glycosylated bridging amino monomers, were found under suitable conditions. These dimers arise from an on-resin cross-linking reaction occurring with the incorporation of a glycoamino submonomer into the growing chain and subsequent nucleophilic attack of the resulting secondary amine to a still unreacted bromoacetylated unit. The arising byproduct can be regarded as a novel dimeric peptoid type.

Asunto(s)

Peptoides/síntesis química , Técnicas de Síntesis en Fase Sólida , Dimerización , Glicosilación , Peptoides/análogos & derivados , Peptoides/química , Conformación Proteica

RESUMEN

Alzheimer's disease (AD) is characterized by the buildup of insoluble aggregated amyloid-ß protein (Aß) into plaques that accumulate between the neural cells in the brain. AD is the sixth leading cause of death in the United States and is the only cause of death among the top ten that cannot currently be treated or cured (Alzheimer's Association, 2011; Selkoe, 1996). Researchers have focused on developing small molecules and peptides to prevent Aß aggregation; however, while some compounds appear promising in vitro, the research has not resulted in a viable therapeutic treatment. We previously reported a peptoid-based mimic (JPT1) of the peptide KLVFF (residues 16-20 of Aß) that modulates Aß40 aggregation, specifically reducing the total number of fibrillar, ß-sheet structured aggregates formed. In this study, we investigate two new variants of JPT1 that probe the importance of aromatic side chain placement (JPT1s) and side chain chirality (JPT1a). Both JPT1s and JPT1a modulate Aß40 aggregation by reducing total ß-sheet aggregates. However, JPT1a also has a pronounced effect on the morphology of fibrillar Aß40 aggregates. These results suggest that Aß40 aggregation may follow a different pathway in the presence of peptoids with different secondary structures. A better understanding of the interactions between peptoids and Aß will allow for improved design of AD treatments.

Asunto(s)

Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Fragmentos de Péptidos/metabolismo , Peptoides/análogos & derivados , Peptoides/farmacología , Agregado de Proteínas/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Amiloide/antagonistas & inhibidores , Amiloide/ultraestructura , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/farmacología , Péptidos beta-Amiloides/ultraestructura , Humanos , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/química , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/ultraestructura , Estereoisomerismo

RESUMEN

Cyclic peptides and their cyclic analogs have received a great deal of attention because of their numerous interesting biological activities and their challenging chemical synthesis. It has also been hypothesized that they might improve the cell permeability compared to linear molecules by providing internal hydrogen bonding and generally decreasing the conformational flexibility. In this study, a series of cyclic and linear peptoid-dexamethasone conjugates were rationally designed and efficiently synthesized on solid-phase for systematic cell permeability studies using reporter gene-based assays. These model compounds should be used to reveal how the cell permeability of cyclic molecules is affected by several physicochemical properties, especially, the reduced conformational flexibility and the ring size. In addition, the synthetic strategy that was adopted in this study can also provide a robust platform for postchemical modifications of various molecular scaffolds in solid-phase or solution-phase syntheses.

Asunto(s)

Permeabilidad de la Membrana Celular/efectos de los fármacos , Técnicas Químicas Combinatorias/métodos , Dexametasona/síntesis química , Dexametasona/farmacología , Péptidos Cíclicos/síntesis química , Peptoides/síntesis química , Peptoides/farmacología , Secuencia de Aminoácidos , Permeabilidad de la Membrana Celular/fisiología , Cromatografía Líquida de Alta Presión , Dexametasona/análogos & derivados , Dexametasona/química , Humanos , Enlace de Hidrógeno , Microondas , Datos de Secuencia Molecular , Estructura Molecular , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Peptoides/análogos & derivados , Peptoides/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción

RESUMEN

Peptoids that inhibit the group I intron RNA from Candida albicans, an opportunistic pathogen that kills immunocompromised hosts, have been identified using microarrays. The arrayed peptoid library was constructed using submonomers with moieties similar to ones found in small molecules known to bind RNA. Library members that passed quality control analysis were spotted onto a microarray and screened for binding to the C. albicans group I intron ribozyme. Each ligand binder identified from microarray-based screening inhibited self-splicing in the presence of 1 mM nucleotide concentration of bulk yeast tRNA with IC(50)'s between 150 and 2200 microM. The binding signals and the corresponding IC(50)'s were used to identify features in the peptoids that predispose them for RNA binding. After statistical analysis of the peptoids' structures that bind, a second generation of inhibitors was constructed using these important features; all second generation inhibitors have improved potencies with IC(50)'s of <100 microM. The most potent inhibitor is composed of one phenylguanidine and three tryptamine submonomers and has an IC(50) of 31 microM. This compound is 6-fold more potent than pentamidine, a clinically used drug that inhibits self-splicing. These results show that (i) modulators of RNA function can be identified by designing RNA-focused chemical libraries and screening them via microarray; (ii) statistical analysis of ligand binders can identify features in leads that predispose them for binding to their targets; and (iii) features can then be programmed into second generation inhibitors to design ligands with improved potencies.

Asunto(s)

Candida albicans/efectos de los fármacos , Intrones/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Peptoides/farmacología , ARN Catalítico/antagonistas & inhibidores , ARN de Hongos/antagonistas & inhibidores , ARN de Transferencia/antagonistas & inhibidores , Animales , Sitios de Unión , Candida albicans/enzimología , Candida albicans/patogenicidad , Relación Dosis-Respuesta a Droga , Ligandos , Conformación Molecular , Biblioteca de Péptidos , Peptoides/análogos & derivados , Peptoides/química , Pneumocystis carinii/efectos de los fármacos , Pneumocystis carinii/genética , Empalme del ARN/efectos de los fármacos , ARN Catalítico/química , ARN Catalítico/genética , ARN de Hongos/química , ARN de Hongos/genética , ARN de Transferencia/química , ARN de Transferencia/genética , Tetrahymena thermophila/efectos de los fármacos , Tetrahymena thermophila/genética

RESUMEN

Peptoids are a non-natural class of oligomers that are composed of repeating N-substituted glycine units and are capable of folding into helices that mimic peptide structure and function. In this letter, we report the concise synthesis of a 1,5-substituted triazole amino acid (Tzl) and its subsequent incorporation into a short peptoid. The Tzl amino acid was shown to induce turn formation in aqueous solution, thus expanding the structural repertoire available to peptoid chemists.

Asunto(s)

Peptoides , Triazoles/química , Modelos Moleculares , Estructura Molecular , Peptoides/análogos & derivados , Peptoides/síntesis química , Peptoides/química , Estructura Secundaria de Proteína , Soluciones/química , Estereoisomerismo , Agua/química

RESUMEN

N-Alkylglycine oligomers (peptoids) constitute a family of non-natural peptidomimetics attractive for the early drug discovery process because of their physicochemical features, easy of adaptation to combinatorial chemistry approaches and their proteolytic stability. Consequently, peptoid libraries have found application for discovering hits against a wide diversity of pharmaceutical targets, among which different examples of antibacterials are found. In the present work, research efforts addressed towards the identification of peptoids as antibacterial agents are discussed.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Técnicas Químicas Combinatorias , Peptoides/farmacología , Animales , Evaluación Preclínica de Medicamentos , Humanos , Pruebas de Sensibilidad Microbiana , Peptoides/análogos & derivados

RESUMEN

This paper describes the design of the highest affinity ligands for Grb2 SH3 domains reported so far. These compounds were designed by combining N-alkyl amino acid incorporation in a proline-rich sequence with subsequent dimerization of the peptoid sequence based on structural data and molecular modeling. Optimization of the linker size is discussed, and the N-alkyl amino acid incorporation into both monomeric halves is reported. Because the affinity for Grb2 of the optimized compounds was too high to be measured using the fluorescent modifications that they induce on the Grb2 emission spectrum, a competition assay was developed. In this test, Grb2 is pulled down from a cellular extract by the initial VPPPVPPRRR peptide bound to Sepharose beads. In the presence of competitors, the test quantifies the amount of Grb2 displaced from the beads. It has enabled us to determine a K(i) value in the 10(-10) M range for the highest affinity Grb2 peptoid analogue dimer.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales , Peptoides/análogos & derivados , Peptoides/metabolismo , Proteínas/química , Proteínas/metabolismo , Dominios Homologos src , Alquilación , Secuencia de Aminoácidos , Animales , Línea Celular , Cricetinae , Dimerización , Proteína Adaptadora GRB2 , Humanos , Datos de Secuencia Molecular , Peptoides/síntesis química , Peptoides/química , Prolina/química , Estructura Terciaria de Proteína , Proteínas/antagonistas & inhibidores , Espectrometría de Fluorescencia , Dominios Homologos src/efectos de los fármacos

RESUMEN

A positional scanning library of N-alkylglycine trimers (peptoids) containing over 10 000 compounds has been synthesized on solid phase. The synthetic pathway involved the use of the submonomer strategy and a set of 22 commercially available primary amines as a chemical diversity source. The unbiased nature of the library allowed its screening against a variety of biological targets, leading to the identification of individual peptoids exhibiting remarkable biological activities (García-Martínez, C. et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2374. Montoliu, et al. J. Pharm. Exp. Therap. 2002, 302, 29. Planells-Cases, R., et al. J. Pharm. Exp. Therap. 2002, 302, 163). In the present work, the screening of this library against a panel of Gram-positive and Gram-negative bacteria led to the identification of different compounds exhibiting antimicrobial activity.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Técnicas Químicas Combinatorias/métodos , Peptoides/química , Peptoides/farmacología , Pruebas de Sensibilidad Microbiana , Biblioteca de Péptidos , Peptoides/análogos & derivados

RESUMEN

A set of terminally protected tripeptoids containing a residue of either N-methylglycine or N-isobutylglycine in position i + 1/i + 2 were synthesized and tested for intramolecularly H-bonded beta-turn formation. By exploiting FT-IR absorption and 1H NMR techniques, their folding tendencies were compared with those of a variety of reference peptides. The amount of beta-turn induction and the relative extent of the various types of intramolecularly H-bonded beta-turn conformers were determined in chloroform solution.

Asunto(s)

Glicina/análogos & derivados , Peptoides/análogos & derivados , Secuencia de Aminoácidos , Cloroformo/química , Glicina/química , Enlace de Hidrógeno , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular/métodos , Peptoides/síntesis química , Peptoides/química , Isoformas de Proteínas , Estructura Secundaria de Proteína , Sarcosina/química , Espectroscopía Infrarroja por Transformada de Fourier