RESUMEN
From an enzymatic perspective, there is a general notion that the bigger and more complex a catalytically active peptide is the more enzyme-like and the better it should become. But is this really true? We have tackled this question firstly by screening split-and-mix-libraries of tri- and tetrapeptides for members that catalyze aldol reactions. Then, the catalytic performance of all possible diastereoisomers of related tri- and tetrapeptidic catalysts of the type H-Pro-Pro-Glu/Asp-NH2 and H-Pro-Pro-Glu/Asp-Pro-NH2 in aldol and conjugate addition reactions was compared.
Asunto(s)
Oligopéptidos/química , Catálisis , Estructura MolecularRESUMEN
The spider venom peptide Huwentoxin-IV (HwTx-IV) 1 is a potent antagonist of hNav1.7 (IC50 determined herein as 17 ± 2 nM). Nav1.7 is a voltage-gated sodium channel involved in the generation and conduction of neuropathic and nociceptive pain signals. We prepared a number of HwTx-IV analogs as part of a structure-function study into Nav1.7 antagonism. The inhibitory potency of these analogs was determined by automated electrophysiology and is reported herein. In particular, the native residues Glu(1), Glu(4), Phe(6) and Tyr(33) were revealed as important activity modulators and several peptides bearing mutations in these positions showed significantly increased potency on hNav1.7 while maintaining the original selectivity profile of the wild-type peptide 1 on hNav1.5. Peptide 47 (Gly(1), Gly(4), Trp(33)-HwTx) demonstrated the largest potency increase on hNav1.7 (IC50 0.4 ± 0.1 nM).
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Venenos de Araña/farmacología , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacología , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Células HEK293 , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Potenciales de la Membrana/efectos de los fármacos , Modelos Moleculares , Datos de Secuencia Molecular , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Venenos de Araña/síntesis química , Venenos de Araña/química , Arañas , Relación Estructura-Actividad , Bloqueadores del Canal de Sodio Activado por Voltaje/síntesis química , Bloqueadores del Canal de Sodio Activado por Voltaje/químicaRESUMEN
Agonists of vasoactive intestinal peptide receptor 2 (VPAC2) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC2. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC2 agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC2 agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides.
RESUMEN
The peptide H-D-Pro-Pro-Glu-NH2 is a highly effective catalyst for conjugate addition reactions between aldehydes and nitroethylene. Only 1 mol % of H-d-Pro-Pro-Glu-NH2 and a 1.5-fold excess of aldehyde with respect to nitroethylene suffice to obtain gamma-nitroaldehydes and, after reduction, monosubstituted gamma-nitroalcohols in excellent yields and optical purities. The products can be readily converted into gamma2-amino acids, thereby opening an effective direct entry into this important class of compounds.
Asunto(s)
Aldehídos/química , Aminoácidos/síntesis química , Etilenos/química , Nitrocompuestos/química , Péptidos/química , Catálisis , Ácido Glutámico/química , Modelos Químicos , Prolina/química , EstereoisomerismoRESUMEN
The separation and detection of small oligopeptides in CE with contactless conductivity detection were demonstrated. A strongly acidic separation buffer (0.5 M acetic acid) was employed in order to render the species cationic. Separation of the stereoisomers was achieved in typically 10-15 min by using either dimethyl-beta-CD (DM-beta-CD), (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (18C(6)H(4)), a combination of the two substances, or of histidine, as buffer additives. Calibration curves were determined for isomers of Gly-Asp and H-Pro-Asp-NH(2), in the range of 0.05-0.5 mM and 0.1-1 mM, respectively, and were found to be linear. LODs were determined to be in the order of 1.0 microM. The determination of isomeric impurities down to about 1% was found possible. Species showing good separation could also be successfully determined on an electrophoretic lab-on-chip device, with analysis times of a few minutes.
Asunto(s)
Conductividad Eléctrica , Electroforesis Capilar/métodos , Oligopéptidos/análisis , Estructura Molecular , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estereoisomerismo , Factores de TiempoRESUMEN
In recent years, oligopeptides have been developed as efficient catalysts for a range of important organic reactions, including acylation, silylation, oxidation, ester hydrolysis and aldol reactions. With many peptidic catalysts, high yields and chiral induction can be achieved under mild reaction conditions. Discovery and optimization of these catalysts typically involves the testing of compound collections and is therefore strongly linked to advances in combinatorial screening methods. This review summarizes recent developments in the field of catalytically active short-chain peptides, highlighting the combinatorial techniques that have facilitated their discovery.
Asunto(s)
Técnicas Químicas Combinatorias , Péptidos/química , Acilación , Catálisis , Hidrólisis , Oxidación-ReducciónRESUMEN
The introduction of a polyethylene glycol chain has become a popular tool for increasing water solubility and bioavailability. Our interest in the development of catalytically active peptides and the selective recognition of peptides has led us to investigate strategies to increase the solubility of peptides in organic solvents. Specifically, we became interested in the introduction of solubilizing moieties at the C-terminus of two peptides. Here we present different synthetic strategies for the preparation of peptide-polyethylene glycol conjugates and discuss the effect of the polyethylene glycol chain on the solubility and other properties, such as the catalytic activity of these peptides.
Asunto(s)
Péptidos/síntesis química , Polietilenglicoles/química , Catálisis , Estructura Molecular , Péptidos/química , Solubilidad , Soluciones/químicaRESUMEN
H-Pro-Pro-Asp-NH2 is a highly active and selective catalyst for asymmetric aldol reactions. Here, the versatility of H-Pro-Pro-Asp-NH2 has been further improved by immobilization on a solid support and functionalization with a short polyethylene glycol linker at the C-terminus. The development, synthesis, and the catalytic properties in aldol reactions of H-Pro-Pro-Asp-resin and H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3 are described. For the solid-supported catalyst, TentaGel with a loading of 0.1-0.2 mmol g(-1) proved to be the optimal support. The solid-supported catalyst can be recycled at least three times without a significant drop in the catalytic activity or selectivity. Using the pegylated catalyst H-Pro-Pro-Asp-Ahx-NH(CH2CH2O)3CH3, only 0.5 mol % are necessary to obtain aldol products in up to 96% yield and 91% enantiomeric excess. In all cases, enantioselectivities are comparable to those obtained with the parent catalyst H-Pro-Pro-Asp-NH2. Thus, immobilization of H-Pro-Pro-Asp-NH2 on Tentagel as well as pegylation led to catalysts with selectivities comparable to the nonmodified catalyst, exhibiting additional distinct advantages such as facile reusability, ease of handling, higher solubility, and thereby greater versatility. handling, higher solubility, and thereby greater versatility.
Asunto(s)
Aldehídos/química , Oligopéptidos/química , Péptidos/química , Tensoactivos/química , Resinas Acrílicas/química , Catálisis , Estructura Molecular , Polietilenglicoles/química , Poliestirenos/químicaRESUMEN
[reaction: see text] Peptides containing a secondary amine and a carboxylic acid in a specific orientation to each other are presented as highly efficient catalysts for asymmetric aldol reactions: (1) their activity is considerably higher compared to that of proline, and (2) the enantioselectivity of the peptidic catalysts can be changed from (R)- to (S)-selectivity by simple modifications of the secondary structure.
Asunto(s)
Aldehídos/química , Aminas/química , Péptidos/química , Catálisis , Estructura Molecular , Prolina/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
1,5-Cyclooctadiene was deprotonated under LICKOR conditions and reacted with Merrifield resin to afford an immobilized cyclooctadiene in high yield. This polymer is effective as a halogen scavenger, while hydroboration leads to a supported 9-BBN analogue. The latter exhibits similar regioselectivity to 9-BBN in olefin hydroboration. [reaction: see text]
Asunto(s)
Alquenos/química , Compuestos de Boro/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Depuradores de Radicales Libres/síntesis química , Polímeros/química , Catálisis , Halógenos/química , Indicadores y Reactivos/síntesis química , Estructura MolecularRESUMEN
An arylsulfonate solid-phase linker is suitable for 'traceless' synthesis and Pd(0) catalyzed cross-coupling reactions.
RESUMEN
[reaction: see text] Room-temperature ionic liquids promote various transition metal-catalyzed reactions in the solution phase. Here, for the first time, we show that these effects are translatable to solid-phase reactions. The Suzuki-Miyaura cross-coupling of 4-iodophenol immobilized on polystyrene-Wang resin with various arylboronic acids was significantly accelerated by the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)(-)]).
Asunto(s)
Técnicas Químicas Combinatorias/normas , Residuos Industriales/prevención & control , Solventes , Boratos/química , Ácidos Borónicos/química , Catálisis , Contaminación Ambiental/prevención & control , Equipo Reutilizado , Imidazoles/química , Yodobencenos/química , Iones , Paladio , Resinas SintéticasRESUMEN
1,5-Cyclooctadiene was lithiated under LICKOR superbase conditions followed by reaction with alkyl halides or ethylene oxide to yield 3-substituted 1,5-cyclooctadienes in high yield and purity. This procedure is suitable for preparation of 1,5-cyclooctadienes carrying pendant functional groups for immobilization on solid-phase resins.