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PubMed1981

Protective effect of muramyl dipeptide analogs against infections of Pseudomonas aeruginosa or Candida albicans in mice.

Two analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide) were found to give better protection than muramyl dipeptide against intraperitoneal Pseudomonas aeruginosa infection or intravenous Candida albicans infection in mice. The analogs tested were N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine and N-acetylmuramyl-L-alpha-amino-butyryl-D-isoglutamine. The optimum treatment was 80 mg/kg per day given once daily for 4 consecutive days before infection by the intraperitoneal, intravenous, or subcutaneous route. Dose response was limited. The compounds were not orally active. Synergism was seen between N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine and gentamicin. No postinfection protection was observed. A nonspecific stimulation of macrophage cells by muramyl dipeptide analogs may contribute to the protection because antiinfective activity against Listeria monocytogenes given intraperitoneally was achieved with CBA mice.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Correlation between in vivo anti-Pseudomonas and anti-Candida activities and clearance of carbon by the reticuloendothelial system for various muramyl dipeptide analogs, using normal and immunosuppressed mice.

A linear correlation coefficient analysis, comparing in vivo anti-infective and reticuloendothelial stimulating activity of several different analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide) suggests that the macrophage is an important target cell for these immunomodulating compounds. The increase in protection against infections of Candida albicans or Pseudomonas aeruginosa in normal or immunosuppressed mice after treatment with 18 different glycopeptides was found to correlate with the degree of clearance of colloidal carbon particles from the blood by the reticuloendothelial system after treatment with the same muramyl dipeptide analogs. The compound which gave the greatest protection in all four assays was N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine followed by N-acetyl-nor-muramyl-L-alanyl-D-isoglutamine. Both analogs were better than the parent muramyl dipeptide. Whether macrophage stimulation alone is responsible for the anti-infective properties of these compounds has not yet been determined.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Immune response to porin in cattle immunized with whole cell, outer membrane, and outer membrane protein antigens of Brucella abortus combined with trehalose dimycolate and muramyl dipeptide adjuvants.

The immune response of cattle to nonliving vaccines derived from Brucella abortus rough strain 45/20 was studied. Vaccines contained trehalose dimycolate and a derivative of muramyl dipeptide. N-acetylmuramyl-L-alpha-aminobutyryl-D-isoglutamine. A factorial experiment was designed to test the effects of type of antigen, quantity of antigen, and quantity of mineral oil on the immune response to porin. Muramyl dipeptide was kept constant at 5 mg per dose, and 1 part of trehalose dimycolate was incorporated for two parts of dry matter. Over a 10-week period, blastogenesis responses to porin were largest in cattle immunized with outer membranes; the highest antibody titers to the porin-lipopolysaccharide complex were achieved by immunization with detergent-extracted outer membrane proteins. There was no advantage in the use of 25, rather than 5, mg of any of the antigens, but antibody responses were improved by increasing the quantity of oil from 0.6 to 1.8 ml per dose. In other animals, blastogenesis and antibody responses were sustained at high levels longer than 3 months after two vaccinations with outer membrane proteins. Intradermal injection of porin evoked inflammatory reactions histologically consistent with delayed-type hypersensitivity. Cross-reactions in cases of delayed-type hypersensitivity occurred with porin derived from a smooth strain of B. abortus but were less extensive than in the blastogenesis test. The magnitude of the delayed-type hypersensitivity and blastogenesis responses induced by vaccination exceeded those observed after natural or experimental infections. No ill effects were observed after vaccination. These findings provide a basis for the use of trehalose dimycolate and muramyl dipeptide adjuvants in evaluating nonviable vaccines for bovine brucellosis.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Granuloma formation by muramyl dipeptide associated with branched fatty acids, a structure probably essential for tubercle formation by Mycobacterium tuberculosis.

Muramyl dipeptide, which does not induce epithelioid granuloma when injected alone dissolved in phosphate-buffered saline, could induce extensive granulomas in guinea pigs when chemically conjugated with branched, but not linear, fatty acids. Peptidoglycan fragments of Staphylococcus epidermidis could evoke epithelioid granulomas when incorporated in a water-in-oil emulsion. These findings suggest the importance of a lipid bound to muramyl dipeptide for granuloma formation. In view of the fact that mycobacteria uniquely contain large amounts of branched fatty acids, it was proposed that the complex of muramyl dipeptide and branched fatty acids, mostly mycolic acids, is a structure in tubercle bacilli responsible for tubercle formation.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1973

Escherichia coli K-12 mutants altered in the transport systems for oligo- and dipeptides.

Two mutants of Escherichia coli K-12, defective in the oligopeptide and dipeptide transport system, are described. A mutant defective in the oligopeptide transport system (opp-1) was isolated as resistant to the inhibitory action of triornithine; this mutant is also resistant to glycylglycylvaline and does not concentrate (14)C-glycylglycylglycine, although it is still as sensitive as the parental strain to glycylvaline and valine. Starting from the opp-1 strain, a mutant defective also in the dipeptide transport system (dpp-1) was isolated; this mutant is resistant to the inhibitory action of glycylvaline, valylleucine, and leucylvaline and does not concentrate (14)C-glycylglycine, although it is still as sensitive as the parental strain to valine. The apparent kinetic constants for oligopeptide and dipeptide transport were measured. The opp marker is co-transducible with trp at 27 min on the E. coli genetic map. The dpp locus is separated from opp and is located between proC (10 min) and opp.

Carbon Radioisotopes↗
PubMed1995

Functional expression of transporter for beta-lactam antibiotics and dipeptides in Xenopus laevis oocytes injected with messenger RNA from human, rat and rabbit small intestines.

A heterologous gene expression system, Xenopus laevis oocytes, was used to prove the intestinal absorption of various beta-lactam antibiotics mediated by an H(+)-dipeptide cotransport system in rat, rabbit and human small intestines. The microinjection of mRNA (messenger RNA) from rat intestine into Xenopus laevis oocytes led to significantly higher uptakes of p.o. active cephalosporins including zwitter-ionic derivatives (cephalexin, cephradine and cefadroxil) and dianionic derivatives (cefixime and ceftibuten) in comparison with oocytes injected with water, whereas the uptake of cefazolin, a parenterally administered derivative, was negligible in both mRNA- and water-injected oocytes. The uptake of cefadroxil was reduced significantly in the presence of dipeptide and various beta-lactam antibiotics, but not in the presence of an amino acid. After sucrose density gradient centrifugation of mRNA, the highest expression of transport activities of both cefadroxil and ceftibuten was observed in the same mRNA fraction with a size of 2.20 to 3.75 kilobases. mRNA-injected oocytes showed a marked pH-dependency in the uptakes of cefadroxil and ceftibuten, whereas water-injected oocytes exhibited only modes uptakes. The most stimulated uptakes of cefadroxil and ceftibuten were observed at an external pH of 5.5 and 5.0, respectively. Furthermore, injection of mRNA isolated from either rat rabbit or human small intestine into oocytes produced significantly higher uptake of cefadroxil and ceftibuten compared with those by oocytes injected with water. Thus, intestinal absorption of p.o. active beta-lactam antibiotics was confirmed to be mediated by an H+ gradient-dependent transport system across the brush-border membrane of rats, rabbits and humans. The carrier-protein for this process is likely a dipeptide transport system.

Animals↗
PubMed1997

The sensitivity of conformational free energies of the alanine dipeptide to atomic site charges.

Different atomic point charge sets are obtained for the alpha R and C7,eq conformations of the alanine dipeptide by fitting the charges of each conformation to the respective ab initio electrostatic potential surfaces both individually and simultaneously, in both the united atom and the all-atom representations. Using these charge sets, the sensitivity of the relative conformational aqueous free energies to the atomic site charges is investigated. For this particular system, we find that the solute-water contributions to the conformational free energy differences have a rather weak dependence on site charges; the calculated intramolecular contributions, however, show a rather strong dependence on the atomic site charges. It is suggested that the calculated results for the alanine dipeptide using a single, simultaneously fit set of charges for both conformations are in better agreement with experiments than the calculations carried out with charges determined individually for each conformation.

Binding Sites↗
PubMed1999

Small dipeptide-based HIV protease inhibitors containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic.

The human immunodeficiency virus (HIV) codes for an aspartic protease known to be essential for retroviral maturation and replication. HIV protease is formed from two identical 99 amino acid peptides. We synthesized [(NHCH2CH2-S-CH2CO)51-52, Ala67,95]HIV-1 protease using the thioether chemical ligation method, and then prepared the [(NHCH2CH2-S-CH2CO)51-52, Ala67,95, Cys98]HIV-1 protease dimer analogue covalently linked by a disulfide bridge. These HIV-1 protease analogues effectively cleaved the Tyr-Phe-type substrate, but had weak affinity to the Tyr-Pro-type substrate. Consequently, the molecular recognition of the protease analogues differs from that of the wild-type enzyme. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing an unnatural amino acid, (2S, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine, with a hydroxymethylcarbonyl (HMC) isostere. The stereochemistry of the hydroxyl group was significant for the enzyme inhibition and the HMC group interacted excellently with the aspartic acid carboxyl groups of HIV protease active site in the essentially same hydrogen-bonding mode as the transition state. Small dipeptide-based HIV protease inhibitors containing the HMC isostere were studied as advantageous compounds. Among them, a dipeptide-based HIV protease inhibitor, KNI-577, exhibited potent antiviral activities, low cytotoxicity, and good pharmacokinetic properties.

Amino Acid Sequence↗
PubMed2001

Separation of dipeptide and tripeptide enantiomers in capillary electrophoresis using carboxymethyl-beta-cyclodextrin and succinyl-beta-cyclodextrin: influence of the amino acid sequence, nature of the cyclodextrin and pH.

The separation of the LL and DD enantiomers of dipeptides and tripeptides using cyclodextrins (CDs) containing carboxyl groups was investigated with respect to the amino acid sequence of the peptides, the nature of the cyclodextrin and the buffer pH. Compared to succinyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin was the more universal CD for enantioseparations. Reversal of the enantiomer migration order upon increasing the buffer pH from 2.5 to 3.5 was observed in some cases. As shown for Phe-Phe reversal of the migration order also occurred between pH 3.5 and 5.3. Complexation constants and complex mobilities change with pH as both, the charge of the peptide and the charge of the CD vary depending on the pH. The complexation constants and complex mobilities of the dipeptides Ala-Phe and Phe-Phe were determined in order to explain the enantiomer migration behavior in the pH range 2.5-5.3. While the complexation constants determined the migration order at pH 2.5 and 5.3, complex mobility had a strong influence around pH 3.5-3.8.

Amino Acid Sequence↗
PubMed2001

Determination of the cis-trans isomerization barrier of several L-peptidyl-L-proline dipeptides by dynamic capillary electrophoresis and computer simulation.

Dynamic capillary electrophoresis (DCE) and computer simulation of the elution profiles with the theoretical plate and the stochastic model has been applied to determine the isomerization barriers of the three dipeptides L-alanyl-L-proline, L-leucyl-L-proline, and L-phenylalanyl-L-proline. The separation of the rotational cis-trans isomers has been performed in an aqueous 70 mM borate buffer at pH 9.5. Interconversion profiles featuring plateau formation and peak broadening were observed. To determine the rate constants k1 and k(-1) of the cis-trans isomerization in dynamic capillary electrophoresis, equations have been derived for the theoretical plate model and stochastic model. The electropherograms were simulated with the ChromWin software which uses the experimental data plateau height h(plateau), peak width at half height Wh, the total migration times of the cis-trans isomers tR and the electroosmotic break-through time t0 as well as the peak ratio [cis]/[trans]. From temperature-dependent measurements, the rate constants k1 and k(-1) and the kinetic activation parameters deltaG#, deltaH# and deltaS# of the cis-trans isomerization of the three dipeptides were obtained.

Computer Simulation↗
PubMed2005

Carnosine and related dipeptides as quenchers of reactive carbonyl species: from structural studies to therapeutic perspectives.

Carnosine (beta-alanyl-L-histidine) and related peptides such as homocarnosine (gamma-amino-butyryl-histidine), balenine beta-alanyl-L-3-methylhistidine) and anserine beta-alanyl-L-1-methylhistidine) are histidine-containing dipeptides (HD) particularly abundant in excitable tissues such as nervous system and skeletal muscle. Although their biochemical role is still unknown, several evidences indicate that these endogenous compounds act as quenchers of reactive and cytotoxic carbonyl species. In this presentation we will review the structural evidences and ex vivo data supporting this hypothesis. We first elucidated the reaction mechanism of carnosine as quencher of alpha, beta-unsaturated aldehydes such as 4-hydroxy-trans-2,3-nonenal (HNE) and acrolein (ACR) and then demonstrated the efficacy of carnosine and related peptides as detoxifying agents of HNE in spontaneously oxidized rat skeletal muscle, by detecting the corresponding HNE-Michael adducts in the crude biological matrix by liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Finally, we set-up and validated a sensitive, selective and specific LC-ESI-MS/MS method for the determination of HD and of the corresponding HNE-Michael adducts to monitor their profile in physiological (aging) and pathological conditions (diabetes, atherosclerosis) characterized by a carbonyl-mediated degenerative overload. The results obtained, beside to give a contribution to the understanding of the biochemical role of histidine-dipeptides, provide a strong rational to the design of novel derivatives, active as exogenous agents able to detoxify carbonyl compounds.

Acrolein↗
PubMed2004

Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units.

It has been shown that fluorinated analogues of naturally occurring biological active compounds including amino acids often exhibit unique physiological activity. Among wide varieties of fluorine-containing amino acids, nonhydrolyzable phosphoamino acids possessing a substituent of the difluoromethylene (CF(2)) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these classes of nonhydrolyzable phosphoamino acids corresponding to pTyr 3, pSer 4, and pThr 5 with their incorporation into peptides using newly developed deprotecting procedures. In this article, stereoselective synthesis of the CF(2)-substituted pThr mimetics and development of a two-step deprotecting methodology for the nonhydrolyzable analogues are reviewed. In the course of the above synthetic study, we found that gamma,gamma-difluoro-alpha,beta-enoates were reduced to gamma-fluoro-beta,gamma-enoates by organocopper reagents and then applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres, which have served as potential dipeptide mimetics having structural as well as electrostatic similarity to the parent peptide bonds. Furthermore, mechanistic investigation of the organocopper-mediated reduction led us to development of a SmI(2)-mediated approach toward the synthesis of the fluoroalkene isosteres.

Biomimetic Materials↗
PubMed2007

Fmoc-based solid-phase synthesis of GPR54-agonistic pentapeptide derivatives containing alkene- and fluoroalkene-dipeptide isosteres.

Fmoc-protected Phe-Gly-type (Z)-alkene dipeptide isostere (ADI) and (E)-fluoroalkene dipeptide isostere (FADI) were synthesized and applied to Fmoc-based solid-phase peptide synthesis (SPPS). These cis-peptide bond mimetics were introduced into a bioactive pentapeptide [H-Amb-Phe-Gly-Leu-Arg-Trp-NH(2); Amb = 4-(aminomethyl) benzoic acid], which has potent GPR54 agonistic activity. The resulting pentapeptide derivatives showed low GPR54 agonistic activity, as compared with the parent peptide and (E)-ADI-containing derivative. This suggests that the trans-amide conformer of Phe-Gly peptide bond of the parent peptide would be significantly important for bioactivity. Contrary to our expectations, a (Z)-FADI-containing derivative exhibited essentially no activity, revealing the necessity of critical validation of FADI-bioisosterism.

Alkenes↗
PubMed1990

The effect of the L-azetidine-2-carboxylic acid residue on protein conformation. I. Conformations of the residue and of dipeptides.

The L-azetidine-2-carboxylic acid (Aze) residue can be incorporated into proteins in the place of L-proline, of which it is the lower homologue. This substitution alters the properties of proteins, especially of collagen. Conformational constraints in N-acetyl-Aze-N'-methylamide and in several dipeptides containing Aze have been analyzed by means of energy computations. They have been compared with peptides containing Pro. The overall conformational preferences of Aze and Pro are similar, but several significant differences occur between them. In general, peptides containing Aze are somewhat more flexible than corresponding peptides containing Pro, because of a decrease in constraints caused by repulsive nonconvalent interactions of the atoms of the ring with neighboring residues. This results in an entropic effect that lessens the stability of ordered polypeptide conformations with respect to the disordered statistical coil. The collagen-like near-extended conformation is energetically less favorable for Aze than for Pro in the single residue and in dipeptides. This effect also contributes to a destabilization of the collagen triple helix. The influence of Aze on the conformation of polypeptides is discussed in the accompanying papers.

Azetidinecarboxylic Acid↗
PubMed2004

Copper(II) complexes containing N,N-donor ligands and dipeptides act as hydrolytic DNA-cleavage agents.

Copper(II) complexes are known to play a significant role in both naturally occurring biological systems and pharmaceutical agents. Recently, Cu(II) complexes have gained importance in DNA cleavage essential for the development of anticancer drugs and chemotherapeutic agents. Therefore, we have designed small molecules, consisting of a metal ion, N,N-donor ligands, and dipeptides, to probe their DNA-cleaving potential. Accordingly, the interaction of Cu(II) with ethylenediamine, histamine and the dipeptides histidylglycine, histidylalanine, and histidylleucine has been investigated. The binding modes, stabilities, and geometries of these complexes were determined by various physicochemical techniques. Their DNA-binding abilities were probed by absorption and fluorescence spectroscopy, and their DNA-cleavage potential was tested by electrophoresis.

Copper↗
PubMed2006

The importance of alkali cations in the [{RuCl2(p-cymene)}2]-pseudo-dipeptide-catalyzed enantioselective transfer hydrogenation of ketones.

We studied the role of alkali cations in the [{RuCl2(p-cymene)}2]-pseudo-dipeptide-catalyzed enantioselective transfer hydrogenation of ketones with isopropanol. Lithium salts were shown to increase the enantioselectivity of the reaction when iPrONa or iPrOK was used as the base. Similar transfer-hydrogenation systems that employ chiral amino alcohol or monotosylated diamine ligands are not affected by the addition of lithium salts. These observations have led us to propose that an alternative reaction mechanism operates in pseudo-dipeptide-based systems, in which the alkali cation is an important player in the ligand-assisted hydrogen-transfer step. DFT calculations of the proposed transition-state (TS) models involving different cations (Li+, Na+, and K+) confirm a considerable loosening of the TS with larger cations. This loosening may be responsible for the fewer interactions between the substrate and the catalytic complex, leading to lower enantiodifferentiation. This mechanistic hypothesis has found additional experimental support; the low ee obtained with [BnNMe3]OH (a large cation) as base can be dramatically improved by introducing lithium cations into the system. Also, the complexation of Na+, K+, and Li+ cations by the addition of [15]crown-5 and [18]crown-6 ethers and cryptand 2.1.1 (which selectively bind to these cations and, thus, increase their bulkiness), respectively, to the reaction mixture led to a significant drop in the enantioselectivity of the reaction. The lithium effect has proved useful for enhancing the reduction of different aromatic and heteroaromatic ketones.

Alkalies↗
PubMed2006

Old molecules for new receptors: Trp(Nps) dipeptide derivatives as vanilloid TRPV1 channel blockers.

The transient receptor potential vanilloid member 1 (TRPV1), an integrator of multiple pain-producing stimuli, is regarded nowadays as an important biological target for the discovery of novel analgesics. Here, we describe the first experimental evidence for the behavior of an old family of analgesic dipeptides, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel blockers. We also report the synthesis and biological investigation of a series of new conformationally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/NMDA selectivity. Compound 15 b, which incorporates an N-terminal 2S-azetidine-derived Arg residue, was the most selective compound in this series. Collectively, a new family of TRPV1 channel blockers emerged from our results, although further modifications are required to fine-tune the potency/selectivity/toxicity balance.

Animals↗