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PubMed1986

Statine-containing dipeptide and tripeptide inhibitors of human renin.

Dipeptide and tripeptide derivatives containing a statine residue were synthesized as inhibitors of human renin. ES-305, bis[(1-naphthyl)methyl]acetyl(BNMA)-histidyl-statine 2(S)-methylbutylamide was found to be a highly potent inhibitor of human renin with a Ki value of 1.7 X 10(-9) M. Dipeptide derivatives with the BNMA group at the N-terminal (BNMA-Val-Sta-isoleucinol [ES-313], BNMA-Leu-Sta-isoleucinol [ES-316], and BNMA-Nle-Sta-isoleucinol [ES-317]) had potencies against human renin that were similar to the potency of ES-305. All these dipeptide derivatives competitively inhibited human renin. The inhibitors were also potent against monkey renin but were less effective against renins from pig, goat, dog, rabbit, and rat. ES-305 had little effect on cathepsin D and pepsin at the concentration of 10(-5) M. The other derivatives showed detectable inhibition of cathepsin D (IC50, 10(-6) - 10(-7) M) and pepsin (10(-5) - 10(-6) M). All the compounds had little or no effect on trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at the concentration of 10(-5) M. Our results indicate that ES-305 is a highly potent and specific inhibitor of human renin. This compound is superior to other, previously described statine-containing renin inhibitors with respect to molecular size and enzyme specificity.

Amino Acids↗
PubMed2001

Preferential utilization of dipeptides by Porphyromonas gingivalis.

Although Porphyromonas gingivalis is known to utilize peptides preferentially, instead of free amino acids, as the source of energy and cell material, there is only limited information on what sizes and kinds of peptide this bacterium preferentially utilizes. In this study, therefore, we tested aspartate or glutamate monopolymers consisting of from 2 to 100 amino acids as metabolic substrates for P. gingivalis. The washed cells of P. gingivalis consumed aspartylaspartate and glutamylglutamate, and produced large amounts of ammonia and organic acids such as propionate and butyrate, while the cells formed only small amounts of end-products from aspartate, glutamate, and other peptides longer than a dipeptide. P. gingivalis also metabolized valylvaline and leucylleucine and produced isobutyrate and isovalerate, respectively, only in the presence of aspartylaspartate or glutamylglutamate. This suggests a metabolic linkage between these dipeptides. These results clearly indicate that P. gingivalis utilizes dipeptides preferentially as its metabolic substrates.

Dipeptides↗
PubMed1993

Dipeptides in parenteral nutrition: from basic science to clinical applications.

The use of intravenous dipeptides shows great promise as an avenue for the provision of amino acids that may otherwise be difficult to deliver via nutrient infusions. The physical/chemical properties and metabolism of numerous dipeptides have now been explored in experimental and human studies. It has been found that these agents have the capacity to spare nitrogen and support serum protein levels in a fashion equivalent to that of intravenous free amino acids. An additional benefit is the ability to deliver certain amino acids that are relatively unstable or poorly soluble in aqueous solutions. These various aspects of intravenous dipeptides are considered in this review.

Animals↗
PubMed2006

Comparison of kinetic characteristics of amino acid-based and dipeptide-based peritoneal dialysis solutions.

UNLABELLED: A mixture of dipeptides (DP) has been proposed as alternatives (to glucose and amino acids, (AA)) osmotic agent in peritoneal dialysis (PD) solutions. DP based solutions may have metabolic and nutritional advantages compared to AA based solutions, as some sources of AA (such as tyrosine) are poorly soluble in water. In a previous study, we compared the kinetic characteristics of DP and AA based solutions; however, the amount of AA differed substantially. The aim of the present study was to compare solutions with almost equal amounts of AA. METHODS: The following solutions were used: (1) amino acid (AA) solution containing leucine, valine, lysine, isoleucine, threonine, phenylalanine and histidine (tyrosine was omitted because of its poor solubility), (2) dipeptide (DP) solution containing leucyl-valine, lysyl-isoleucine, threonyl-phenylalanine and histidyl-tyrosine. Sixteen Sprague-Dawley rats were divided in two groups and were subjected to intraperitoneal injection of either 25 mL of AA (n=8) or DP solution. Dialysate and blood samples were taken frequently postinfusion for measurement of AA and DP concentrations as well as AA from DP. RESULTS: Kinetic models were developed for estimation of diffusive mass transport coefficient between peritoneal cavity and blood (K BD), DP hydrolysis rate coefficient (K H) and AA clearance in the body (K C). Calculations showed that K H is about ten times lower than K BD. Thus, hydrolysis rate in peritoneal cavity is much lower than the diffusive transport rate of DP. K BD for AA appeared to be similar to K BD for dipeptides. K C was much higher than K BD for AA. This finding explains the rapid clearance of amino acids from blood. Nevertheless, the AA-based solution resulted in much higher peak concentrations of AA in blood after 120 min of the dwell than AA concentrations achieved following the use of the DP-based solution. CONCLUSIONS: Peritoneal transport characteristics of AA and DP were similar; however their kinetics in blood differs substantially. The DP solution resulted in a less pronounced increase in AA concentrations in blood, suggesting that DP solution could provide AA in a more physiological way.

Amino Acids↗
PubMed2005

3H-L-histidine and 65Zn(2+) are cotransported by a dipeptide transport system in intestine of lobster Homarus americanus.

The tubular intestine of the American lobster Homarus americanus was isolated in vitro and perfused with a physiological saline whose composition was based on hemolymph ion concentrations and contained variable concentrations of (3)H-l-histidine, (3)H-glycyl-sarcosine and (65)Zn(2+). Mucosa to serosa (M-->S) flux of each radiolabelled substrate was measured by the rate of isotope appearance in the physiological saline bathing the tissue on the serosal surface. Addition of 1-50 micromol l(-1) zinc to the luminal solution containing 1-50 micromol l(-1) (3)H-l-histidine significantly (P<0.01) increased M-->S flux of amino acid compared to controls lacking the metal. The kinetics of M-->S (3)H-l-histidine flux in the absence of zinc followed Michaelis-Menten kinetics (K(m)=6.2+/-0.8 micromol l(-1); J(max) =0.09+/-0.004 pmol cm(-2) min(-1)). Addition of 20 micromol l(-1) zinc to the luminal perfusate increased both kinetic constants (K(m)=19+/-3 micromol l(-1); J(max)=0.28+/-0.02 pmol cm(-2) min(-1)). Addition of both 20 micromol l(-1) zinc and 100 micromol l(-1) l-leucine abolished the stimulatory effect of the metal alone (K(m)=4.5+/-1.7 micromol l(-1); J(max)=0.08+/-0.008 pmol cm(-2) min(-1)). In the absence of l-histidine, M-->S flux of (65)Zn(2+) also followed the Michaelis-Menten relationship and addition of l-histidine to the perfusate significantly (P<0.01) increased both kinetic constants. Addition of either 50 micromol l(-1) Cu(+) or Cu(2+) and 20 micromol l(-1) l-histidine simultaneously abolished the stimulatory effect of l-histidine alone on transmural (65)Zn(2+) transport. Zinc-stimulation of M-->S (3)H-l-histidine flux was significantly (P<0.01) reduced by the addition of 100 micromol l(-1) glycyl-sarcosine to the perfusate, as a result of the dipeptide significantly (P<0.01) reducing both l-histidine transport K(m) and J(max). Transmural transport of (3)H-glycyl-sarcosine was unaffected by the presence of either l-histidine or l-leucine when either amino acid was added to the perfusate alone, but at least a 50% reduction in peptide transport was observed when zinc and either of the amino acids were added simultaneously. These results show that (3)H-l-histidine and (65)Zn(2+) are cotransported across the lobster intestine by a dipeptide carrier protein that binds both substrates in a bis-complex (Zn-[His](2)) resembling the normal dipeptide substrate. In addition, the transmural transports of both substrates may also occur by uncharacterized carrier processes that are independent of one another and appear relatively specific to the solutes used in this study.

Animals↗
PubMed1993

Studies of HIV-1 protease inhibitors. II. Incorporation of four types of hydroxyethylene dipeptide isosteres at the scissile site of substrate sequences.

Human immunodeficiency virus type 1 (HIV-1) protease inhibitors containing four types of hydroxyethylene dipeptide isosteres were designed and synthesized. These inhibitors consist of eight stereoisomers of phenylalanylproline (Phe-psi[H.E.]-Pro), four stereoisomers of phenylalanylalanine [Phe-psi[H.E.]-Ala), and one stereoisomer each of phenylalanylglycine (Phe-psi[H.E.]-Gly) and cyclohexylalanylalanine (Cha-psi[H.E.]-Ala) hydroxyethylene dipeptide isosteres. For the synthesis of the latter two isosteres, a newly developed synthetic method for gamma-lactone was applied. The inhibitory activities of these peptides were evaluated by cleavage assay of partially purified gag proteins or purified synthetic peptide. Of the inhibitors examined, compounds 2c (Z-Asn-(2S,3R,4S,5S)-Phe-psi[H.E.]-Pro-NHB(un); Bu(n) = n-butyl, Ki = 0.50 microM), 21a (Z-Asn-(2R,4S,5S)-Phe-psi[H.E.]-Ala- NHBu(n), Ki = 0.34 microM) and 23 (Z-Asn-(2R,4S,5S)-Cha-psi[H.E.]-Ala- NHBu(n), Ki = 0.46 microM) were moderately potent inhibitors. The results revealed that the alkyl substituent at C2 is essential, and the stereochemistry of the hydroxyethylene dipeptide isosteres greatly affected their inhibitory activities.

Amino Acid Sequence↗
PubMed1994

Synthetic dipeptide, N-stearoyl-D-Ser-L-Pro-OEt, induces release of tissue-type plasminogen activator in cultured cells and in experimental animals.

The tissue-type plasminogen activator (t-PA)-releasing action of synthetic dipeptides containing Gly, Ser or Pro was investigated. Among 10 dipeptides, Boc-L-Ser-L-Pro-OH and H-L-Ser-L-Pro-OH induced t-PA release in vitro, but the others were inactive. Since Boc-L-Ser-L-Pro-OH was more effective than H-L-Ser-L-Pro-OH, 7 related dipeptides with N-acylation were synthesized. Five of them enhanced the release of t-PA; N-stearoyl-L-Ser-L-Pro-OH (FK-5) had the greatest effect. Four compounds were further examined for activity to enhance the release of t-PA in rats. FK-5 produced a two-fold increase in fibrinolytic activity, and N-palmitoyl-L-Ser-L-Pro-OH (FK-4) also markedly enhanced the release of t-PA. Since FK-5 caused severe hemolysis, 7 analogues of FK-5 were synthesized. All of them enhanced the release of t-PA from melanoma (Bowes) cells. In rats, FK-5, N-stearoyl-D-Ser-L-Pro-OH (FK-8) and N-stearoyl-D-Ser-L-Pro-OEt (FK-10) enhanced the fibrinolytic activity two-fold. FK-5 and FK-8 also exhibited strong hemolytic activity, but FK-10 did not induce hemolysis. Therefore, FK-10 was examined in rabbits. After the injection of this compound, the fibrinolytic activity in the euglobulin fraction was markedly enhanced without accompanying hemolysis. Thus, FK-10 potently enhances fibrinolytic activity both in vitro and in vivo.

Amino Acid Sequence↗
PubMed2005

Interaction between quaternary ammonium ions and dipeptides: positive anion allosteric effect.

The binding properties of dipeptides possessing aromatic residues towards quaternary ammonium ions have been investigated by 1H-NMR spectroscopy. The intermolecular hydrogen bonding between exchangeable protons (OH and NH) of aromatic residues of dipeptides and the counter anion of ammonium ion is the primary force. After the formation of the intermolecular hydrogen bonding, two aromatic residues of dipeptides can provide pi-base cavity to interact with the quaternary ammonium moiety.

Allosteric Regulation↗
PubMed2000

193 nm photolysis of aromatic and aliphatic dipeptides in aqueous solution: dependence of decomposition quantum yield on the amino acid sequence.

The values of molar absorption coefficient and quantum yields of photodecomposition and peptide bond scission were determined for a number of aromatic and aliphatic dipeptides under 193 nm laser irradiation in neutral argon-saturated aqueous solution. Under these conditions we could show that no dependence of the dipeptide decomposition quantum yield on the sequence of amino acid residues exists, neither for aromatic dipeptides nor for aliphatic ones.

Amino Acid Sequence↗
PubMed2006

An analog of a dipeptide-like structure of FK506 increases glial cell line-derived neurotrophic factor expression through cAMP response element-binding protein activated by heat shock protein 90/Akt signaling pathway.

Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.

Animals↗
PubMed2003

Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives.

The strategy of using small peptides for effective targeting of tumor cells in chemotherapy has proven beneficial. Recently we showed that J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester), an alkylating nitrogen mustard-containing dipeptide, exhibited strong cytotoxic activity in fresh human tumor samples in addition to rapid and pronounced inhibition of macromolecular syntheses and cellular respiration in the human tumor lymphoma cell line U-937 GTB. In this study, an additional series of 17 nitrogen mustard-containing dipeptides has been synthesized and analyzed for cytotoxic activity in a panel of 10 human tumor cell lines. The results were compared to the single amino acid mustard derivative melphalan and its ethyl and isopropyl esters. Also P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester), a tripeptide that previously has shown impressive effects in human tumor cells, was used as reference. The tested compounds displayed various activities in the different cell lines but also showed a high correlation, indicating a similar mechanism of action. Factors like amino acid composition, amino acid sequence, modifications of the C- and N-termini, and to a minor extent the lipophilicity of the dipeptide derivatives appear to influence the in vitro activity. The results indicate that the activity of these compounds not only relies on their chemical reactivity, but also on active biological interactions such as transport across membranes and/or enzymatic liberation of reactive molecular entities.

Alkylation↗
PubMed1975

Jejunal and ileal absorption of dibasic amino acids and an arginine-containing dipeptide in cystinuria.

Ileal transport of dibasic amino acids has not previously been studied in the intestine of healthy volunteers or cystinuric patients. Experiments have therefore been designed to compare ileal and jejunal absorption of lysine and arginine both in normal subjects and cystinuric patients. In addition, jejunal perfusion experiments have been carried out to investigate absorption of the dipeptide L-arginyl-L-leucine. The results indicate that, at the concentrations studied (4.2 mM lysine, 1 mM arginine), severe transport defects exist throughout the whole small intestine for both amino acids in cystinuria. Despite the transport defect for free arginine, cystinuric patients absorbed the dipeptide L-arginyl-L-leucine normally. Because of the transport defect for free arginine, it has been possible to show that during absorption of L-arginyl-L-leucine in cystinuria approximately 30% of dipeptide-bound arginine can be recovered from the gut lumen in the free form. These findings indicate that the prime function of specific amino acid transport systems during the absorption of protein digestion products may be as a "recapture mechanism" for amino acids liberated as a result of mucosal cell peptide hydrolysis.

Adult↗
PubMed1999

[Glutamine dipeptide enriched enteral nutrition improving gut permeability in sever burns].

OBJECTIVE: To determine the effect of glutamine dipeptide on gut permeability in severe burns. METHODS: Twenty-four severe burn patients were randomly divided into two groups: control group and GLN group. All patients received enteral nutrition for 12 days after burn. Both groups were isocaloric and isonitrogen. GLN group patients were given nutrition solution enriched with glutamine dipeptide at a dosage at 0.5 g.kg-1.day-1 (equivalent to L-glutamine 0.3 mg.kg-1.day-1). On the day 1 and 12 after burn, the plasma amino acid was measured by a standard amino acid analyzer. On the day 1, 3, 6 and 12, the gut permeability was detected with Lactulose and Manitol assay by HPLC-PED, and then wound healing rate of burn area was determined on the day 30 and hospital stay was recorded. ANOVA was done for data analysis. RESULTS: The plasma GLN concentrations decreased in both groups on day 1, (control group: 361.3 +/- 70.8 microns/L, GLN group: 348.6 +/- 52.5 microns/L, P = 0.624, normal value: 659.5 +/- 35.0 microns/L), and the GLN group showed high plasma GLN concentration on day 12 (566.4 +/- 128.3 microns/L), with significant difference between control group (417.6 +/- 74.8 microns/L, P = 0.002). On day 1, L/M ratio value was the highest in both groups. On day 3, L/M ratio in the GLN group became lower than that of control group, and returned to normal on day 6 and maintained to day 12. There were significant differences of wound healing rate between the two groups and the length of hospital stay on day 30 (CONTROL GROUP: (81 +/- 7)%, GLN group: (89 +/- 7)%, 0.018) (CONTROL GROUP: 68 +/- 27 days, GLN group: 49 +/- 13 days, P = 0.049). CONCLUSION: The glutamine-dipeptide enriched enteral nutrition can improve the plasma GLN level after severe burn, decrease the gut permeability from early stage, ameliorate wound healing rate on day 30, and reduce hospital stay.

Adolescent↗
PubMed2002

Oxazole- and imidazole-based Ser-Leu dipeptide mimetics in potent inhibitors of antigen presentation by MHC class II DR molecules.

Imidazole and oxazole derivatives 1 to 4 were designed and prepared as dipeptide mimetics to replace the Ser-Leu dipeptide sequence of Ro-25-9980 (Ac-(Cha)-RAMA-S-L-NH2), a peptidic inhibitor of antigen binding to major histocompatibility complex (MHC) class II DR molecules linked to rheumatoid arthritis (RA). The most potent analog in binding assays (IC50 = 30 nM in DRB1*0401 binding; 1.6 times as potent as Ro 25-9980) was 16, Ac-(Cha)RAMA-(S)S-psi(oxazole)-L-NH2. The SAR of peptide hybrids 10 to 24, prepared by incorporating the dipeptide mimetics 1 to 4 is discussed. Of these hybrids, 23 and 24, analogs that incorporated the imidazole and oxazole mimetics as well as optimized variants at positions 3 to 5, were found to have 70 to 80 nM binding affinity comparable to the parent peptide in DRB 1*0401 binding and were also active in DRB1*0101 binding, while being resistant to proteolysis by cathepsin B. Both of these compounds showed inhibitory activity in an antigen-stimulated T-cell proliferation assay, indicating their potential to suppress autoimmune responses and as leads for therapeutic agents to treat RA.

Antigen Presentation↗
PubMed2002

[The effects of glutamine dipeptide on the improvement of endotoxemia in severely burned patients].

OBJECTIVE: To explore the influence of glutamine dipeptide on the plasma endotoxin levels in severely burned patients. METHODS: Thirty burned patients with TBSA of 30 - 70% and III degree burn area more than 20% were randomly divided into control (C) and study (S) groups. Glutamine dipeptide powder in dose of 0.5 g/kg/day was given orally in bolus to those patients in S group during 1 - 12 postburn days (PBDs). The plasma levels of glutamine were determined during 1 - 12 PBDs. Simultaneously, the plasma endotoxin level was detected on 1, 3, 6 and 12 PBDs. The wound healing rate at 30 PBD and total hospital stay days were recorded. RESULTS: The plasma glutamine levels at 1 PBD in C and S groups were obviously lower than normal level (659.5 +/- 35 micromol/L), but there was no difference between these two groups (P > 0.05). The plasma glutamine levels in C group was much lower than that in S group at 12 PBD (P < 0.05). The plasma endotoxin concentration on 1 PBD in these two groups increased evidently compared with the normal value (P < 0.05), and there was no difference between the two groups (P > 0.05). The plasma endotoxin level in S group was much lower than that in C group on 3 PBD (P < 0.05). As for the wound healing rate at 30 PBD, it was markedly higher in S group than that in C group (91% vs 85%). On the other hand, the hospital stay days in S group were evidently lower than that in C group (52 vs 67). CONCLUSION: Oral intake of glutamine dipeptide in burn patients could be beneficial to the maintenance of the plasma concentration of glutamine and in decreasing plasma endotoxin level. It would also enhance the wound healing rate at 30 PBD and shorten the hospital stay days.

Adolescent↗
PubMed1992

[Effect of glutamine and glutamine-dipeptide enriched amino acid solution on rat small bowel mucosa regeneration].

To mine the effects of glutamine and it's dipeptide enriched nutrition solution on the gastro-intestinal structure and protein metabolism, 40 male Wistar rats were studied for 8 days. The rats were randomly divided into four groups: sham operation group, standard amino acid solution group, glutamine enriched group and glutamine dipeptide enriched group. Observation parameters were: weight change; serum AA profile analysis; computerized morphometric analysis of mucosa thickness and villus height; total nitrogen balance; and liver, kidney functional results. The data were managed by multiple sample comparison methods (ANOVA of Statview 512 software) on Macintosh PC. Significant level was put on P < 0.05. The results showed that significant differences of body weight, serum glutamine level, nitrogen balance, intestinal mucosa thickness and villus height were found between the control and study groups. No significant difference in liver and kidney function was found. Gln-Ala dipeptide had same effects as free glutamine did.

Amino Acids↗
PubMedDate not supplied

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

The aminosuccinyl (Asu) residue is formed as intermediate in some peptide and protein reactions. Potential energy calculations, using the parameters of the empirical conformational energy program for peptides (ECEPP), were performed on blocked X-Asu dipeptides, where X = Gly, Ala, Ser, Val and Pro. Results indicate that intra-residue interactions are dominant, and the low-energy dipeptide conformations correspond to the low-energy single-residue minima. Comparisons were made with previous results from energy calculations on blocked Asu-X dipeptides (X = Gly, Ala, Ser and Val).

Dipeptides↗
PubMed1992

The unprocessed C-terminal dipeptide of recombinant beta-nerve growth factor determines three stable forms with distinct biological activities.

The processing of polypeptide neurotrophins in the nervous system is poorly understood. In this paper, we provide information on the effects of C-terminal processing of nerve growth factor. Three forms of recombinant mouse beta-nerve growth factor (rNGF) were produced and isolated from insect cells infected with a recombinant baculovirus. The three purified forms of rNGF exhibited distinct biological activities and differed in their abilities to compete with high affinity binding of mouse beta-nerve growth factor (mNGF). However, they were chemically and structurally indistinguishable from each other. All three forms of rNGF differed from mature mNGF from mouse submaxillary gland in that the C-terminal Arg-Gly dipeptide had not been proteolytically removed. Removal of the C-terminal dipeptide by gamma-NGF peptidase treatment converted the three forms into a single form identical with mature mNGF. The above results demonstrate that a single polypeptide of rNGF, due to the presence of a C-terminal dipeptide, exhibits three stable dimeric protein conformations with distinct biological activities. The apparent lack of gamma-NGF peptidase in the nervous system raises the possibility that the biologically significant form of NGF may differ from mature mNGF; such a difference may be of physiological relevance.

Animals↗