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PubMed2004

[HIV reproduction inhibition by amino acid and dipeptide derivatives of fullerene C60].

Target-aimed synthesis of a new class of water soluble amino acid and dipeptide derivatives of fullurene (C60 - X) for inhibition of specific virus enzymes, i.e. protease and reverse transcriptase of HIV (P HIV and RT HIV) in cell culture lytic and chronic infections was performed. Out of 13 tested substances, 8 showed inhibitory activity and 5 were effective in pharmacological doses (ID50 varied within 0.46 to 1.0 mcm/ml with respect to the lytic infection and 5.0 to 12.5 mcm/ml with respect to the chronic infection). The activity of (1), (2), (6), (7) and (8) was comparable to that of azidothymidine, a nucleozide inhibitor of RT HIV in the cell culture lytic infection. The substances also showed marked virucidal action. The cytotoxicity (survival, antiproliferative effect) varied from low to very low with respect to the rapidly dividing cells MT4 and HTHIV27 (CD50 > 200-800) and was somewhat higher with respect to PBL (CD50 > 100). The selectivity index (SI = CD50/ID50) was equal to 165-2000 for various samples. The prototype derivatives (1) and (2) had a selective (competitive) inhibitory action on the recombinant protease of HIV with IC50 = 1.25-2.76 mcM, while derivatives (1), (la) and (2) had a noncompetitive inhibitory action on the recombinant reverse transcriptase of HIV (Ki = 7.9-12.1 mM). The pharmacokinetic study of the prototype derivative (1) on laboratory animals revealed no acute or chronic toxicity up to the terminal high concentrations. As for (1), its high interspecies (mice--rabbits) relative bioavailability equal to 110% was shown.

Amino Acids↗
PubMedDate not supplied

Caspase-3 activation and induction of PARP cleavage by cyclic dipeptide cyclo(Phe-Pro) in HT-29 cells.

BACKGROUND: Cyclo(Phe-Pro) has been shown to inhibit cancer cell growth and induce apoptosis in HT-29 colon cancer cells. MATERIALS AND METHODS: The molecular mechanisms mediating cyclo(Phe-Pro)-induced apoptosis in HT-29 cells were investigated. Cells were treated with 5 mM or 10 mM cyclo(Phe-Pro) for varying times. Immunoblot analysis was used to detect poly(ADP-ribose)polymerase (PARP) cleavage. A fluorescence-based enzymatic assay was used to measure caspase-3 activity. RESULTS: Cyclo(Phe-Pro) (10 mM) induced time-dependent cleavage of PARP, detected as early as 8 hours post treatment. PARP cleavage was blocked by co-administration with the broad-range caspase inhibitor Z-VAD-FMK Cyclo(Phe-Pro) also induced a time-dependent increase (p < 0.01) in caspase-3 activity. This increase in activity was blocked in the presence of the caspase-3 inhibitor Ac-DEVD-CHO. CONCLUSION: These results provide evidence that cyclo(Phe-Pro)-induced apoptosis in HT-29 cells is mediated by a caspase cascade. These findings warrant further investigation into the potential antitumour activity of cyclo(Phe-Pro) and its related cyclic dipeptide derivatives.

Amino Acid Chloromethyl Ketones↗
PubMed2005

[Effects on glutathione of patients received glutamine dipeptide enriched parenteral nutrition post abdominal surgery].

OBJECTIVE: To observe the effects of glutamine (GLN) enriched parenteral nutrition (PN) on glutathione level, immune function, liver function, infectious complication and hospital stay of patients undergone abdominal operation. METHODS: Forty patients with abdominal surgical disease undergoing elective surgical treatment were randomly divided into two groups (study and control group). All patients received total parenteral nutrition (TPN) for up to 7 days perioperatively. The control group received TPN while the study group received TPN including GLN dipeptide. Both groups received isonitrogen and isocaloric nutrition. Nonprotein caloric intake is 83.6 kJ.kg(-1).day(-1), glycogen: lipid ratio is 7:5, nitrogen intake is 0.16 g.kg(-1).d(-1), calories:nitrogen ratio is 489 kJ:1 g. RESULTS: The decreasing degree of glutathione levels of plasma and red blood cell in study group is lower than that in control group postoperatively. GSH/GSSG ratio of plasma in study group is higher than that in control group on 3rd day postoperatively (53 +/- 11 vs 31 +/- 7, F = 4.725, P = 0.001). Albumin (ALB) of both groups decreased slightly postoperatively. ALB level of study group was higher than that of control group on 3rd day postoperatively [(3.8 +/- 0.4) g.dl(-1) vs (3.4 +/- 0.4) g.dl(-1), F = 2.128, P = 0.02]. No significant differences were noted between immunoglobin (IgG, IgM and IgA) and T lymphocyte subgroup (CD4, CD8, CD4/CD8) levels of both groups postoperatively. There was no infectious complication in study group, while one in control group. There was shorten trend of hospital stay in study group compared with control group [(22.3 +/- 2.1) d vs (24.9 +/- 1.7) d, t = -0.935, P = 0.32]. CONCLUSIONS: Glutamine enriched PN has the trend of maintaining glutathione level of plasma and red blood cell in patients having undergone abdominal operation, and can sustain GSH/GSSG ratio and ALB level, protect antioxidant ability, promote liver function postoperatively. Glutamine enriched PN has the trend of shortening hospital stay, decreasing incidence of infectious complication.

Abdomen↗
PubMed2006

Enteral feeding of glycyl-glutamine dipeptide improves the structure and absorptive function of the small intestine after allogenetic liver transplantation in rats.

BACKGROUND: Recipients of liver transplantation could have postoperative structural injury and declined absorptive function in the gastrointestinal tract. Glutamine (Gln) is a special nutrient of small intestinal mucosa and of various kinds of cells proliferating rapidly. But Gln could form a kind of poisonous pyroglutamic acid in water solution, which is the limitation of Gln in clinical practice. Glycyl-glutamine (Gly-Gln) is highly soluble and can be hydrolyzed to release glutamine. This study was undertaken to observe the effect of Gly-Gln dipeptide by enteral feeding on the intestinal structure and absorptive function after allogenetic liver transplantation in rats. METHODS: Twelve male inbred Lewis rats were selected randomly as donors, and 24 male inbred BN rats as recipients of allogenetic liver transplantation. The recipients were also randomly divided into two groups: control group (ALA group, n=12) and experimental group (GLN group, n=12). In each group, 6 normal BN rats were sampled as the normal parameter on the 3rd preoperative day. The 6 recipients in the control group received alanine 0.6 g/kg daily for 3 days before operation and 7 days after operation by gastric perfusion, and the 6 recipients in the experimental group were given Gly-Gln 0.6 g/kg daily the same way. The 12 BN recipients underwent 3-day fasting (free access to water with 0.23% sodium chloride) and orthotopic liver transplantation in aseptic conditions and were given subcutaneous injection of CsA 2 mg/kg daily after the operation. The 12 BN recipients were sampled on the 8th postoperative day. All of the 24 BN rats were subjected to examination of mucosal structure, activities of Na+-K+-ATP and disaccharidase, and D-xylose absorption test. RESULTS: The 12 BN recipients were alive after liver transplantation. On the 3rd preoperative day, mucosal structure, activities of Na+-K+-ATP and disaccharidase and D-xylose absorption in the two groups were not significantly different. On the 8th postoperative day, the parameters of the two groups were markedly changed compared with those on the 3rd preoperative day. However, the parameters of GLN group were remarkably higher than those of ALA group. CONCLUSION: Enteral feeding of Gly-Gln could improve the structure and absorptive function of the small intestine after liver transplantation in rats.

Animals↗
PubMed1991

Stereocontrolled synthesis of psi[CH = CH] dipeptide isosteres.

A new stereocontrolled synthesis of the psi[CH = CH] dipeptide isostere is described. They key step of the sequence relies on the stereospecific alpha-alkylation of delta-amino-gamma-mesyloxy-alpha,beta-unsaturated esters. The broad availability of nucleophilic alpha-side chains by this method allows the preparation of a wide variety of psi[CH = CH] isosteres with predictable stereochemistry.

Alkylation↗
PubMed1990

Effect of leu-(Asp, Asn, Glu, Gln) dipeptides on platelet aggregation in vitro.

A series of Leu-(Asp, Asn, Glu, Gln) dipeptides were synthesized and tested for their effect on human platelet aggregation in vitro induced by collagen, ADP, or adrenaline. It was found that only Leu-Asp-NH2 and Leu-Asn-NH2 inhibit rather strongly platelet aggregation, whereas a small inhibition was observed with Leu-Glu-NH2 and Leu-Gln-NH2, respectively.

Adenosine Diphosphate↗
PubMedDate not supplied

Conformation of aminosuccinyl dipeptides Ac-Asu-X-NHMe from empirical energy calculations.

Conformational energy calculations were carried out on the N-acetyl-N'-methylamides of aminosuccinyl (Asu) peptides. Computations were performed using a procedure analogous to that of the ECEPP/2 program, on N-Ac-L-Asu-NMe, N-Ac-L-Asu-L-X-NHMe, where X = Gly, Ala, Ser, Val and N-Ac-D-Asu-L-Ala-NHMe. With the exception of N-Ac-L-Asu-L-Val-NHMe, the lowest-energy forms of all the dipeptides correspond to a beta-bend conformation of type II' or II for a L,L and D,L sequence, respectively. When X = Val, the folded conformation is destabilized, and more extended conformations are preferred. The puckering of the cyclic imide has a small but meaningful influence on the relative energies of the minima. The calculations were shown to be in agreement with available experimental data.

Dipeptides↗
PubMed1990

Synthesis of N-(phosphonoacetyl)-dipeptide derivatives and evaluation of their antihypertensive activity.

A series of N-(phosphonoacetyl)-dipeptide derivatives was synthesized for pharmacological testing as antihypertensive compounds. Several of these compounds demonstrated a moderate antihypertensive effect in Wistar spontaneous hypertensive rats (SHR) with p.o. dosing. ACE inhibition by the compounds was studied using ACE from rat plasma and lung. Inhibitors containing esterified C-termini are pro-drugs and showed activity only for plasma ACE.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Phenylalanine and tyrosine metabolism in renal failure: dipeptides as tyrosine source.

Several lines of evidence suggest that tyrosine formation is impaired in renal failure. The concentration of tyrosine is decreased and the phenylalanine/tyrosine ratio is increased in plasma and in skeletal muscle cells. After an oral or intravenous load, the rise of plasma phenylalanine is augmented, the clearance is decreased, oxidation is diminished and the corresponding rise of plasma tyrosine level is blunted. Tyrosine elimination and oxidation are not altered in uremia. The defect in tyrosine formation may be especially important in uremic patients on a low protein diet supplemented with tyrosine-free essential amino acid preparations and in subjects on artificial nutritional support. Thus, tyrosine should be regarded as a conditionally essential amino acid in renal failure and should be supplied exogenously, at least in these patient groups. Oral tyrosine supplementation was shown to replete plasma and intracellular pools and improve nitrogen balance in chronic renal failure patients on a low protein diet. However, because of poor solubility in aqueous solutions, tyrosine cannot be included in the free form in amino acid solutions for parenteral nutrition. To circumvent stability or solubility problems, tyrosine containing dipeptides and/or N-acetyl-tyrosine may serve as tyrosine sources for parenteral supply. Renal failure does not affect alanyl-tyrosine hydrolysis, and there is an immediate increase of plasma tyrosine concentration after peptide infusion. Elimination and hydrolysis of glycine-tyrosine is retarded in renal failure, but the clearance exceeds clinically relevant infusion rates. After infusion of N-acetyl-tyrosine, no increase in plasma tyrosine is seen, and the half-life N-acetyl-tyrosine is grossly prolonged in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

A dipeptide insertion in domain I of exotoxin A that impairs receptor binding.

Deletions within the structural exotoxin A gene of 27 or 119 amino acids in domain I of the mature polypeptide, or of 88 or 105 amino acids in domains I and II, resulted in the synthesis of exotoxin A (ETA) polypeptides that were not secreted from Pseudomonas aeruginosa hosts but were localized in the cell membrane. Insertions of a hexanucleotide sequence, either pCGAGCT or pCGAATT, at TaqI sites within the gene resulted in variant exotoxin A polypeptides which were secreted normally. pCGAGCT causes insertion of either Glu-Leu or Ser-Ser in the amino acid sequence of the toxin, while pCGAATT causes insertion of either Glu-Phe or Asn-Ser dipeptides. Although the cytotoxicity of eight variants was unimpaired, that of four others was reduced, and one variant which had a Glu-Phe insert between residues 60 and 61 (ETA-60EF61) was 500-fold less cytotoxic than wild-type exotoxin A. Purified ETA-60EF61 dissociated much faster from mouse LMTK- cells than wild-type ETA, suggesting that the insertion impaired the ability of ETA-60EF61 to interact with exotoxin A receptors. The location of the insert is within a major concavity on the surface of domain I of the exotoxin A molecule, suggesting that this concavity is important for toxin-receptor interaction.

ADP Ribose Transferases↗
PubMed1989

An orally active renin inhibitor: cyclohexylnorstatine-containing dipeptide (KRI-1314).

In our continuing search for low molecular weight, human renin inhibitors, a dipeptide derivative, morpholino-naphthyl-acyl-histidyl-cyclohexyl-norstatine (KRI-1314), was newly synthesized and estimated for oral effectiveness. This compound inhibited plasma renin from humans and from Japanese monkeys in vitro, with 50% inhibitory concentrations (IC50) of 4.7 x 10(-9) and 2.4 x 10(-8) mol/l, respectively. The mean blood pressure of sodium-depleted Japanese monkeys was lowered significantly after intravenous injection or oral administration of KRI-1314. The maximum reduction was attained 3 h after oral administration at a dose of 10 mg/kg. Plasma renin activity (PRA) was halved 1 h after oral administration of KRI-1314, and this inhibition persisted for more than 5 h. results suggest that KRI-1314, a potent, orally effective and long-lasting renin inhibitor, may become one of a new class of antihypertensive agent.

Administration, Oral↗
PubMed1989

Effect of various chemical modifiers on H+ coupled transport of cephradine via dipeptide carriers in rabbit intestinal brush-border membranes: role of histidine residues.

We examined the effect of diethylpyrocarbonate (DEPC), a histidine specific reagent, on H+ coupled transport of cephradine via dipeptide carriers in the intestinal brush-border membranes, in comparison with the effects of other chemical modifiers. Pretreatment of membrane vesicles with DEPC resulted in the inhibition of cephradine transport in the presence or absence of an inward H+ gradient. This inhibition was reversed by subsequent treatment with hydroxylamine, but not with dithiothreitol. The inactivation by DEPC pretreatment was abolished by the presence of cephradine or glycylsarcosine. In the DEPC-pretreated membranes, the V(max) value of cephradine uptake was decreased without any change in the Km value. In contrast, cephradine uptake was not changed by the pretreatment with N-acetylimidazole, a tyrosine specific reagent, or p-chloromercuribenzene sulfonate, a sulfhydryl reagent. These results suggest that histidine residues in the carriers are essential for H+ coupled transport of amiocephalosporins.

Animals↗
PubMed1988

Transpeptidation reactions of porcine pepsin. Formation of tetrapeptides from dipeptide substrates.

Pepsin-catalyzed transpeptidation was studied by high resolution 75 MHz 13C nuclear magnetic resonance spectroscopy. Enrichment with 13C at the carbonyl carbons of the substrates Leu-Tyr-NH2 and Leu-Leu-NH2 facilitated detection and identification of the transpeptidation and hydrolysis products of enzymic action. Porcine pepsin was found in each case to synthesize and release the tetrapeptide Leu-Leu-Leu-Leu as the primary product of transpeptidation, the longest oligomeric product of transpeptidation observed to date. Productive binding of the dipeptide substrates into the active site groove of pepsin required an induction period of several minutes. Quenching experiments suggested the presence of strongly bound intermediate forms of Leu and Leu-Leu prior to observation of any enzyme-free products. The finding of the tetrapeptide as a primary product is discussed as an instance where transpeptidation of the tripeptide competes successfully with the action of pepsin subsite S3 as a trigger for product release.

Animals↗
PubMedDate not supplied

[Conformation of lanthanide complexes with Schiff bases of pyridoxal and dipeptides].

In order to simulate the active centres of pyridoxal enzymes, lanthanide complexes of pyridoxal-dipeptide (gly-asn) azomethines were investigated by means of NMR 1H and optical spectroscopy. NMR spectra were shown to correspond to conformation averaged over two positions of the ion. The ion was bound to the oxygen atom of PL and nitrogen atom of azomethine. In addition, it coordinates the oxygen atom of the peptide bond or the asparagine carboxyl.

Dipeptides↗
PubMed1988

Ergothioneine, histidine, and two naturally occurring histidine dipeptides as radioprotectors against gamma-irradiation inactivation of bacteriophages T4 and P22.

Bacteriophages P22, T4+, and T4os (osmotic shock-resistant mutant with altered capsids) were diluted in 0.85% NaCl and exposed to gamma irradiation (2.79 Gy/min) at room temperature (24 degrees C). T4+ was more sensitive to inactivation than was P22, and the T4os mutant was even more sensitive than T4+. Catalase exhibited a strong protective effect and superoxide dismutase a weaker protection, indicating that H2O2 or some product derived therefrom was predominant in causing inactivation of plaque formation. Low but significant (0.1-0.3 mM) reduced glutathione (GSH) enhanced phage inactivation, but a higher (1 mM) GSH concentration protected. A similar effect was found for the polyamine, spermidine. In contrast, 0.1 mM L-ergothioneine (2-thiol-L-histidine betaine) exhibited strong protection and 1 mM afforded essentially complete protection. L-Ergothioneine is present in millimolar concentrations in some fungi and is conserved up to millimolar concentrations in critical tissues when consumed by man. L-Histidine and two histidine-containing dipeptides, carnosine and anserine, protected at a concentration of 1 mM, a level at which they are present in striated muscles of various animals.

Anserine↗
PubMed1986

[Biological role of histidine-containing dipeptides].

The biological role of histidine-containing dipeptides is reviewed. The role of carnosine and anserine in muscle function is discussed from the evolutionary viewpoint. Evidence on the antioxidative effect of carnosine and its protection of biological membranes against lipid peroxidation-induced damages is presented. The effects of presently known natural antioxidative agents and carnosine on lipid peroxidation are compared. Carnosine has been shown to be a more universal protector of membranes as compared to free radical scavengers.

Animals↗
PubMed1985

Models of molecular evolution. 2. Stereospecificity of dipeptide syntheses by means of cyanamides and carbodiimides.

Acetyl, benzyloxycarbonyl and tosyl protected DL-alanine, DL-leucine, DL-methionine, DL-phenylalanine, and DL-valine were condensed with DL-amino acid methyl esters. Cyanamide, diethylcyanamide, diisopropyl carbodiimide, dicyclohexyl carbodiimide, and N-cyclohexyl-N'-(2-morpholino ethyl) carbodiimide-N''-methotosylate served as condensing reagents. Water, methanol, and dimethylformamide were used as reaction media. The stereochemical course of these dipeptide syntheses was elucidated by means of 13C-n.m.r. spectroscopy. The formation of L-L and D-D bonds (isotactic sequences) was favoured in ca. 80% of all condensations. L-L/L-D (D-D/D-L) ratios of up to 6:1 were found.

Dipeptides↗
PubMedDate not supplied

[Aspartame--the sweet-tasting dipeptide--does not affect the pancreatic insulin-secreting function].

The action of a synthetic dipeptide aspartam (150 to 180 times as sweet as glucose) on pancreatic insulin-secretory function of rats was studied in vivo and in vitro. The drug was given orally while drinking (300 mg/kg body weight) or was added to the incubation medium of cultivated pancreatic cells (20 mM). It was shown that insulin content in the rat blood serum remained unchanged 10 and 35 minutes after aspartam administration. The drug did not exert any stimulating effect upon insulin secretion following the addition to the pancreatic cell culture medium. It is concluded that aspartam exhibits no direct or mediated action on pancreatic insulin-secretory function.

Animals↗