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PubMed1982

Effects of muramyl dipeptide on superoxide anion release and on anti-microbial activity of human macrophages.

Exposure of human monocyte derived macrophages to muramyl dipeptide in vitro increased phorbol myristate acetate-stimulated O2- release by these cells; the activity of such macrophages against Toxoplasma gondii or against Staphylococcus aureus was not increased. The failure of muramyl dipeptide to enhance human macrophage anti-microbial activity correlated with the failure of muramyl dipeptide to enhance O2- release in response to phagocytic stimuli. These results and those previously published by others indicate that muramyl dipeptide may enhance release of certain inflammatory mediators (O2- and endogenous pyrogen) without enhancing the anti-microbial activity of human macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed1998

X-ray structures of new dipeptide taste ligands.

The molecular basis of sweet taste was investigated by carrying out the crystal state conformational analysis by X-ray diffraction of the following dipeptide taste ligands: N-3,3-dimethylbutyl-aspartylphenylalanine methyl ester, I (N-DMB-Asp-Phe-OMe), its sodium salt (N-DMB-Asp-Phe-ONa), II, aspartyl-D-2-aminobutyric acid-(S)-alpha-ethylbenzylamide, III (Asp-D-Abu-(S)-alpha-ethylbenzylamide), aspartyl-N'-((2,2,5,5-tetramethylcyclopentanyl)-carbonyl)-(R)- 1,1-diamino-ethane, IV (Asp-(R)-gAla-TMCP), and aspartyl-D-valine-(R)-alpha-methoxymethylbenzyl amide, V (Asp-D-Val-(R)-alpha-methoxymethylbenzylamide). With the exception of the sodium salt II, all compounds are sweet-tasting, showing in some cases considerable potency enhancement with respect to sucrose. The results of this study confirm the earlier model that an 'L-shape' molecular array is essential for eliciting sweet taste for dipeptide-like ligands. In addition, it was established that (i) substitution of the N-terminal group does not inhibit sweet taste, if its zwitterionic character is maintained; (ii) a hydrophobic group located between the stem and the base of the L-shape could be responsible for sweetness potency enhancement, as found in I, III and IV; in fact, the extraordinary potency of the N-alkylated analogue I would support a model with an additional hydrophobic binding domain above the base of the 'L'; (iii) removal of the methyl ester at the C-terminus of compound I with the salt formation gives rise to the tasteless compound II; (iv) for the first time all possible side-chain conformers (g-, g+ and t) for the N-substituted aspartyl residue were observed; and (v) a retro-inverso modification, incorporated at position 2 of the dipeptide chain, confers greater flexibility to the molecule, as demonstrated by the contemporary presence of six conformationally distinct independent molecules in the unit cell and yet sweet taste properties are maintained, as found in IV.

Computer Simulation↗

PubMed1999

Enantiomeric separation of glycyl dipeptides by capillary electrophoresis with cyclodextrins as chiral selectors.

Uncharged cyclodextrins were tested as chiral selectors for the enantiomeric separation of 13 glycyl dipeptides with capillary electrophoresis. Initial experiments were performed on 10 mmol/L of a cyclodextrin in 0.1 mol/L phosphoric acid -0.088 mol/L triethanolamine. Some of the resolved dipeptides were nonaromatic, which is noteworthy since, to our knowledge, no examples of the separation of small, nonaromatic molecules have been published. Mobility difference plots for Gly-DL-Leu and Gly-DL-Phe with heptakis(2,6-di-O-methyl)-beta-cyclodextrin showed relatively flat profiles in a large concentration range, which is an advantage for the development of robust quantitative analytical methods. The use of a background electrolyte (BGE) solution with pH 3.0 gave irreproducible results for two of the dipeptides, the acidic Gly-DL-Asp and Gly-DL-Glu; this pH is not advisable for the development of robust methods for these two peptides. The need for purer chiral selectors was demonstrated by comparing different batches of heptakis(2,6-di-Omethyl)-beta-cyclodextrin from the same supplier. A BGE consisting of malonic acid and triethanolamine was introduced to give better buffer capacity than the original BGE at pH 3.0.

Buffers↗

PubMed1994

Parenteral glutamine dipeptide supplementation does not ameliorate chemotherapy-induced toxicity.

BACKGROUND: Glutamine-supplemented total parenteral nutrition (TPN) improved the nitrogen balance in catabolic situations. In animal studies, parenteral glutamine supplementation appeared to maintain gut integrity. This study was performed to evaluate the possible positive effects of glutamine supplementation in catabolic hematologic patients. METHODS: This was a prospective double-blind placebo-controlled pilot study, in which 20 treatment cycles in unselected hematologic patients with intensive chemotherapy were studied. Glutamine was given as a dipeptide. Patients were randomized per treatment cycle to receive isonitrogenous TPN (0.272 g nitrogen/kg of body weight) and isoenergetic TPN (2200 kcal NPE/day) without or with 40 g L-alanyl-L-glutamine (26 g glutamine) until the neutrophil count was greater than 0.5 x 10(9)/L. The daily oral food intake was recorded and analyzed carefully. Toxicity grades for performance status, mucositis, and diarrhea were scored according to the World Health Organization classification. RESULTS: No differences in neutropenic period, fever, extra antibiotics, and toxicity scores were observed, except for a gain in body weight per treatment cycle in favor of the glutamine-supplemented TPN. No side effects or allergic reactions were noted after the dipeptide administration. CONCLUSION: Supplementation of glutamine dipeptide was safe but had no significant positive clinical effect.

Adult↗

PubMed2001

PEPT1-mediated uptake of dipeptides enhances the intestinal absorption of amino acids via transport system b(0,+).

Free amino acids and short chain peptides are the main digestion products of dietary proteins in the small intestine. Whether there is a direct interference in transport of both groups of degradation products is not known. We used human intestinal Caco-2 cells to investigate whether the absorption of dipeptides by the peptide transporter PEPT1 alters the apical uptake of free cationic and neutral amino acids. Influx of L-[3H]Arg into Caco-2 cells was Na+-independent and mediated mainly by the b(0,+) system recognizing both cationic and neutral amino acids. Preincubation of cells with 10 mM of selected neutral, mono- or dicationic dipeptides increased the influx of L-Arg up to fourfold. Preloading with equivalent concentrations of the corresponding free amino acids also increased L-Arg influx but dipeptides always proved to be more efficient. The observed trans-stimulation was found to be specific for cationic amino acids since transport of L-[3H]Ala remained unaffected. We here demonstrate for the first time a direct interplay in amino acid and peptide transport in intestinal cells that may selectively alter the kinetics of amino acid absorption.

Alanine↗

PubMed1989

Analgesic dipeptides. VI.: Synthesis and structure-activity relationships of N-terminal modified analogues of the analgesic compounds H-Xaa-Trp(Nps)-OMe (Xaa=Lys, Orn, Arg).

In order to determine the influence of the N-terminal amino group of the dipeptide derivatives H-Xaa-Trp(Nps)-OMe[Xaa = Lys (2a), Orn (2b), Arg (2c)] on their antinociceptive effects, the syntheses of their corresponding deaminated, acetylated and dimethylated analogues have been achieved. Deamino and dimethyl analogues of 2a,b,6a,b, and 18a,b were prepared by coupling the corresponding N omega-Z- and N omega-Z-N alpha-Me2 amino acids with H-Trp-OMe, using the DCC/HOSu method, followed by sulfenylation of the resulting compounds and removal of the Z groups. Guanidylation of 6b and 18b provided the arginine analogues 6c and 18c, respectively. Ac-Xaa-Trp(Nps)-OMe [Xaa = Lys (11a), Orn (11b) were synthesized by acetylation of H-Xaa(Z)-Trp(Nps)-OMe with acetic anhydride, in the presence of 4-dimethylaminopyridine, and subsequent removal of the Z groups. Coupling of Ac-Arg-OH.HC1 with H-Trp-OMe, using the DCC/HOSu procedure, followed by sulfenylation of the resulting 8:3 diastereomeric mixture of L,L and L,D dipeptides afforded Ac-ambo-Arg-Trp(Nps)-OMe 11c+11d. The antinociceptive effects of 6a-c, 11a-d, and 18 a-c were evaluated after i.c.v. administration in mice. The N alpha-acetyl dipeptides 11 were found to exhibit a naloxone-reversible antinociceptive effects comparable with those of 2, while N-deaminated and N,N-dimethylated analogues were inactive.

Analgesics↗

PubMed1976

The mass spectrometric identification of dipeptide mixtures obtained from dipeptidylaminopeptidase. I--Hydrolysates.

The amino acid sequence of a polypeptide can be deduced by an identification of all the dipeptides obtained from a Dipeptidylaminopeptidase I hydrolysate of the original polypeptide and its des N-terminal amino acid derivative. The components of such dipeptide mixtures can be readily identified from the chemical ionization (helium) mass spectra of their N-ethoxycarbonylpropenyl methyl ester derivatives without prior separation. The pyrolytic conversion of N-protected peptide dimethyltrideuteromethyl anilinium salts to their methyl esters in the direct insertion probe of a mass spectrometer was found to be most suitable for the derivatization of such dipeptide mixtures.

Amino Acid Sequence↗

PubMed2006

1,3,5-Triazepane-2,6-diones as structurally diverse and conformationally constrained dipeptide mimetics: identification of malaria liver stage inhibitors from a small pilot library.

The development of the 1,3,5-triazepane-2,6-dione system as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics is reported. The synthesis of the densely functionalized 1,3,5-triazepane-2,6-dione skeleton was achieved in only four steps from a variety of simple linear dipeptide precursors. To extend the practical value of 1,3,5-triazepane-2,6-diones, a general polymer-assisted solution-phase synthesis approach amenable to library production in a multiparallel format was developed. The conformational preferences of the 1,3,5-triazepane-2,6-dione skeleton were investigated in detail by NMR spectroscopy and X-ray diffraction. The ring exhibits a characteristic folded conformation which was compared to that of related dipeptide-derived scaffolds including the more planar 2,5-diketopiperazine (DKP). Molecular and structural diversity was increased further through post-cyclization appending operations at urea nitrogens. Preliminary biological screens of a small collection of 1,3,5-triazepane-2,6-diones revealed inhibitors of the underexplored malaria liver stage and suggest strong potential for this dipeptide-derived scaffold to interfere with and to modulate biological pathways.

Combinatorial Chemistry Techniques↗

PubMed2006

Sequence-dependent binding of dipeptides by an artificial receptor in water.

An artificial dipeptide receptor (1) was designed and observed to bind the deprotonated dipeptide Ac-D-Ala-D-Ala-OH in buffered water with K = 33,100 M(-1), whereas other dipeptides such as Ac-Gly-Gly-OH or Ac-D-Val-D-Val-OH were bound less efficiently, by factors of more than 10 (K < 3000 M(-1)). The efficient binding and the pronounced sequence selectivity are the result of a combination of strong electrostatic contacts and size-discriminating hydrophobic interactions. To provide such a combination, a guanidiniocarbonylpyrrole cation was attached to a novel cyclotribenzylene-substituted alanine derivative 5, to provide a hydrophobic bowl-shaped cavity just large enough to bind a methyl group but not any larger alkyl chains, thus causing the receptor to prefer alanine to valine. We describe the synthesis of 1 and the evaluation of its complexation properties in UV and fluorescence titration studies.

Binding Sites↗

PubMed2007

Microporous organic materials from hydrophobic dipeptides.

In the last few years dipeptides with two hydrophobic residues (hydrophobic dipeptides) have emerged as an unexpected source of stable microporous organic materials. Supramolecular self-assembly of the rather small building blocks is dictated by stringent demands on the hydrogen-bond formation by the peptide main chains and the aggregation of hydrophobic entities in the side chains. A systematic survey of structures derived from single-crystal X-ray diffraction studies has revealed the existence of two large classes of structures, differing in the dimensionality of the hydrogen-bonding patterns in the crystals and the nature of the channels. The present review summarizes the structural properties of the microporous dipeptides and discusses their potential applications.

Dipeptides↗

PubMed2005

Stereoselective acylation of a racemic amine with C(alpha)-methyl phenylglycine-based dipeptide 5(4H)-oxazolones.

Reactions of a racemic amine with chiral, N(alpha)-acetylated, C(alpha)-methyl l-phenylglycine-based dipeptide 5(4H)-oxazolones proceed diastereoselectively to give predominantly dipeptide alkylamides comprising d-alpha-phenylethylamine. Diastereoselectivity is remarkably sensitive to solvent polarity and reaction temperature but not significantly to the nature of the C(alpha)-tetrasubstituted alpha-amino acid at position 1 of the dipeptide. The beta-turn 3D structures of the aminolysis products were established in CDCl(3) solution by FT-IR absorption and in one case in the crystal state by X-ray diffraction as well.

Acylation↗

PubMed1995

Monoclonal anti-dipeptide antibodies cross-react with detyrosinated and glutamylated forms of tubulins.

Two monoclonal antibodies, GLU-1 and A1.6, raised against gamma-L-glutamyl-L-glutamic acid dipeptide (Glu-Glu) and Ca(2+)-dependent ATPase from Paramecium, respectively, recognized the dipeptide Glu-Glu sequence. Whereas the antibodies immunofluorescently stained very few, if any, cytoskeletal fibers in cultured mammalian cells, almost all interphase as well as mitotic spindle microtubules became visible after treatment of cells with carboxypeptidase A. Immunoblot analysis demonstrated intense cross-reaction of the antibodies to the alpha-tubulin subunit. alpha-Tubulin isotypes produced as fusion proteins in bacteria were labeled by both the antibodies only when the proteins did not contain a tyrosine residue at the C terminus, indicating that GLU-1 and A1.6 specifically recognize the detyrosinated form of alpha-tubulin. When microtubule protein purified from brain was probed, not only alpha-but also, to a lesser extent, beta-tubulin were revealed by the dipeptide antibodies. A synthetic tripeptide YED containing one glutamyl group linked to the second residue of the peptide via the gamma position was also recognized by the antibodies. Since this peptide sequence corresponds to the amino acid sequence of polyglutamyated class III beta isotype at amino acid position 437 to 439, it is suggested that GLU-1 and A1.6 are able to recognize the glutamylated form of beta-tubulin. These results indicate that the C-terminal Glu-Glu sequence displays strong antigenicity, and the antibodies recognize the sequence present in the C terminus of the detyrosinated form of alpha-tubulin and the glutamyl side chain of beta-tubulin. Particularly strong immunoreaction was detected with ciliary and flagellar microtubules; thus, stable axonemal microtubules appear to be rich in post-translationally modified tubulin subunits.

Animals↗

PubMed1990

Use of parenteral dipeptides to increase serum tyrosine levels and to enhance catecholamine-mediated neurotransmission.

The use of intravascular tyrosine (TYR) to enhance catecholamine release in hemorrhagic shock and other cardiovascular diseases, or as a constituent of nutrient mixtures used for total parenteral nutrition, is limited by the unusually poor solubility of the amino acid in water. We have thus examined the ability of various TYR-containing dipeptides, which are more water soluble than the amino acid, to raise serum TYR, to restore blood pressure in hemorrhaged hypotensive rats, and to lower blood pressure in spontaneously hypertensive rats (SHR). L-Tyrosyl-L-proline (TYR-PRO), L-tyrosyl-L-alanine (TYR-ALA), L-alanyl-L-tyrosine (ALA-TYR), and L-tyrosyl-L-tyrosine (TYR-TYR) given intravenously (12.5-25 mg/kg) all caused significant increases in serum TYR; the increase after TYR-PRO was dose related in the range 12.5-50 mg/kg. All of the dipeptides also caused significant elevations in blood pressure among hypotensive rats when administered intraarterially. Moreover, given intraperitoneally (100 mg/kg), all of them also lowered blood pressure in SHRs. These observations suggest that TYR-containing dipeptides may be useful in some clinical situations where maintaining or elevating blood TYR levels would be desirable.

Animals↗

PubMed2003

Synthesis and conformational investigation of cyclic dipeptides: 7-membered rings containing alpha- and beta-amino acids.

The synthesis of heterocyclic compounds containing the 7-membered ring system [1,4]diazepane-2,5-dione is described. The aim of this study was to elaborate the solid phase and solution synthesis of eight representatives of the cyclic scaffold and to investigate their chemical stability and their conformational properties. The solid phase synthesis was performed on aminomethyl polystyrene resin using 5-(4-formyl-3,5-dimethoxyphenoxy)valeric acid as a backbone linker system (BAL-linker). After attachment of the alpha- and beta-amino acid and deprotection of the amino function, the dipeptide ester was obtained. The molecule was cyclized on the solid support by treatment with NaOMe in MeOH/NMP. The product was cleaved from the resin by TFA. For the solution pathway the linear dipeptides were synthesized by coupling of the BOC-protected L-alpha-amino acid with the beta2-amino acid ester (EDC/HOBT). After N- and C-terminal deprotection of the dipeptide, the linear species was cyclized with EDC/HOBT at a concentration of 3 mM in DMF. The products showed high chemical stability after storage in DMSO at room temperature for weeks. The x-ray and two dimensional NMR investigations were performed to investigate the conformation of the molecules. Three types of configuration could be distinguished by NMR, depending on the substitution pattern of the cyclic compounds. The x-ray results confirmed the NMR observations. In general the 7-membered rings showed rigidity, thus they could represent optimal scaffolds for new receptor ligands.

Amino Acids↗

PubMed1993

Gamma-linked dipeptide analogues of 2-desamino-2-methyl-N10-propargyl-5,8- dideazafolate as antitumour agents.

Our search for water-soluble quinazoline TS inhibitors that are transported into cells via the RFC, but are not substrates for FPGS, led us to the synthesis of dipeptide analogues of ICI 198583 diglutamate. Although a number of dipeptide analogues were active against isolated TS and L1210 cells in vitro, lack of in vivo stability was a problem. This was circumvented by the synthesis of modified dipeptides where either the alpha-carboxyl of the second amino acid was removed (alpha'-COOH) e.g. -L-glu-GABA or where the second amino acid was the unnatural D-enantiomer e.g.-L-glu-D-glu. Further studies were performed with the -L-glu-D-glu and its 7-CH3, 2'F modified analogue, demonstrating that they use the RFC for cell entry but are not active through polyglutamate formation. The latter compound was tested against experimental tumour models and found to have good activity.

Animals↗

PubMed2007

A molecular dynamics study of Cyclophilin A free and in complex with the Ala-Pro dipeptide.

Six different molecular dynamics simulations of Cyclophilin A, three with the protein free in water and three with the Ala-Pro dipeptide bound to the protein, have been performed, and analysed with respect to structure and hydration of the active site. The water structure in the binding pocket of the free Cyclophilin A was found to mimic the experimentally obtained binding cis conformation of the dipeptide. Cyclophilin A is a peptidyl-prolyl cis-trans isomerase (PPIase), but the mechanism of the cis/trans isomerization is not exactly clear. This study was performed to understand better the binding between dipeptide and Cyclophilin A, but also two previously proposed isomerization mechanisms are discussed.

Binding Sites↗

PubMed2005

Electroaffinity in paracellular absorption of hydrophilic D-dipeptides by sparrow intestine.

We previously demonstrated size selectivity in the absorption of nonelectrolyte hydrosoluble probes in birds, presumably by the paracellular pathway. Our goal in this study was to determine the charge selectivity in the absorption of hydrosoluble D-dipeptides, because there have been no studies of the electroaffinity of this absorption pathway in birds. For this purpose isosmotic solutions with two hydrophilic D-dipeptides: serine-lysine (positive at pH 7.4) and serine-aspartic (negative at pH 7.4) were gavaged into the stomach in nonanesthetized house sparrows (Passer domesticus), and injected into the pectoralis with a syringe in different trials. Fractional absorption was calculated as F = [AUC by gavage)]/[AUC by injection] (AUC = area under the curve of plasma probe concentration vs. time). Fractional absorption was significantly higher for the positively charged than negatively charged dipeptide (respectively, F=0.30+/-0.05 vs. F=0.17+/-0.03). These findings give the first evidence of cation selectivity by the paracellular route in the absorption of hydrosoluble solutes in the small intestine in birds.

Animals↗

PubMed2002

Optimal absorptive transport of the dipeptide glycylsarcosine is dependent on functional Na+/H+ exchange activity.

Optimal nutrient absorption across the intestinal epithelium is dependent on the co-ordinated activity of a number of membrane transporters. Di/tripeptide transport across the luminal membrane of the intestinal enterocyte is mediated by the H(+)-coupled di/tripeptide transporter hPepT1. hPepT1 function is dependent on the existence of a pH gradient (maintained, in part, by the action of the Na(+)/H(+) exchanger NHE3) across the apical membrane of the small intestinal epithelium. The physiological problem addressed here was to determine how two transporters (hPepT1 and NHE3), involved in nutrient absorption and pH(i) homeostasis, function co-operatively to maximise dipeptide absorption when both operate sub-optimally at typical mucosal surface pH values (pH 6.1-6.8). Functional hPepT1 activity in human intestinal epithelial (Caco-2) cell monolayers was determined by measurement of apical uptake and apical-to-basolateral transport of the dipeptide glycylsarcosine. The dependence of hPepT1 on NHE3 activity was measured (either after Na(+) removal or addition of the NHE3-selective inhibitor S1611) using both Caco-2 cell monolayers and hPepT1-expressing Xenopus laevis oocytes. Apical glycylsarcosine uptake in Caco-2 cell monolayers was modulated by apical pH, extracellular Na(+), incubation time and S1611. Uptake in hPepT1-expressing oocytes was independent of Na(+) or S1611. We conclude that functional NHE3 activity is required to allow optimal absorption of dipeptides across the human intestinal epithelium.

Absorption↗