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At least 649 records · Page 36Linked to original sources

PubMed2000

Peptides affecting coagulation.

Based on amino acid sequence similarities that exist between the fibrinogen gamma-chain and kappa-casein, and also functional similarities between milk and blood coagulation, considerable effort has been made to investigate the effects of milk proteins and peptides on platelet function and thrombosis. In particular, a number of peptides derived from the glycomacropeptide segment of kappa-casein, have been shown to inhibit platelet aggregation and thrombosis. KRDS, a peptide from lactoferrin has also been shown to inhibit platelet aggregation but to a lesser extent than its fibrinogen analogue RGDS. Despite their functional and structural similarities they do not act in the same way on platelet function and are thought to affect thrombus formation differently. Further investigation is needed to determine if these milk-derived bioactive peptides are released naturally following ingestion and might therefore be useful as the basis for milk-based products with anti-thrombotic properties.

Animals↗

PubMedDate not supplied

Extending insulin action in vivo by conjugation to carboxymethyl dextran.

The biochemical and pharmacological properties of bioactive peptides and proteins can be altered by conjugation with polymers. This report describes site-specific attachment of insulin to activated carboxyl groups of carboxymethyl dextran (CMD, MW=51000) through the GlyA1 insulin amino group. On average, three or four insulin molecules were grafted to a CMD linear chain. Coupled insulin molecules were properly folded, and the bioactivity of conjugated insulin in the blood glucose depression assay was 9.6 IU/mg, which was only 2.6 times less than that for native insulin. The cell growth study indicated that the CMD-insulin conjugate was as mitogenic as insulin on vascular smooth muscle cells, whereas the starting CMD polymer was not. The insulin receptor binding constant of the conjugate (3.6 x 10[9] M[-1]) compared well with that of native insulin (7.6 x 10[9] M[-1]), indicating that the CMD chain does not present any major constraints to binding. Plasma clearance of CMD-insulin obeyed a two-compartment pharmacokinetic (PK) model with a CMD-insulin conjugate plasma elimination half-life of 114.1 min, which was significantly longer than that of soluble Zn-insulin (12.4 min). In contrast, pharmacodynamic (PD) profiles (blood glucose lowering effects) after intravenous (iv) administration of the conjugate or insulin in rats were not different. Subcutaneous (sc) administration of the conjugate resulted in a significantly prolonged plasma profile with a noncompartmental PK parameter mean residence time (MRT) of 103.5 min which was significantly longer than that of soluble Zn-insulin (40.5 min). This was reflected in the protracted PD effect of sc administered conjugate with time needed to reach minimum glucose concentration Tnadir of 95.7 min, which was significantly longer than that of insulin (62 min). We conclude that the conjugation of insulin to CMD leads to a bioactive conjugate with a delayed sc PD profile showing prolonged response, resembling intermediate acting insulin preparations.

Animals↗

PubMed2000

Conformational restriction through C alpha i <--> C alpha i cyclization: Ac12c, the largest cycloaliphatic C alpha,alpha- disubstituted glycine known.

Two complete series of N-protected, monodispersed oligopeptide esters to the pentamer level from 1-aminocyclododecane-1-carboxylic acid (Ac(12)c), an alpha-amino acid conformationally constrained through C(alpha)(i) <--> C(alpha)(i) cyclization, and either L-Ala or Aib residues, along with the N-protected Ac(12)c homopeptide alkylamide series from monomer to trimer, have been synthesized by solution methods and fully characterized. The solution-preferred conformations of these peptides have been assessed by Fourier transform ir absorption and (1)H-nmr techniques. Moreover, the molecular structures of one derivative (Z-Ac(12)c-OH) and three peptides [the tripeptide ester Z-L-Ala-Ac(12)c-L-Ala-OMe, the tripeptide alkylamide Z-(Ac(12)c)(3)-NHiPr, and the tetrapeptide ester Z-(Aib)(2)-Ac(12)c-Aib-OtBu (Aib, alpha-aminoisobutyric acid)] have been determined in the crystal state by x-ray diffraction. The results obtained point to the conclusion that beta-bends and 3(10)-helices are preferentially adopted by peptides based on Ac(12)c, the largest cycloaliphatic C-disubstituted glycine known. A comparison with the structural tendencies extracted from published works on peptides from Aib, the prototype of C-disubstituted glycines, and the other extensively studied members of the class of 1-aminocycloalkane-1-carboxylic acids (Ac(n) c, with n = 3-9), is made and the implications for the use of the Ac(12)c residue in the Ac(n) c scan approach of conformationally restricted analogues of bioactive peptides are briefly discussed.

Alanine↗

PubMed1997

Preparation of peptide and protein powders for inhalation.

Innovations in biotechnology and recombinant techniques have led to a large increase in the number of macromolecule drugs developed over the last several years. These molecules are enabling new therapies for many previously untreated or poorly treated diseases. Due to poor oral absorption, most biopharmaceuticals are delivered by injection. Medical science, health care providers and consumers have been searching for alternative methods of delivering macromolecule drugs. Animal and human clinical studies have demonstrated that pharmacological doses of bioactive peptides and proteins pass, by a natural biological process, from the lungs into the bloodstream or local tissue. New macromolecule drugs are also being developed for treatment of respiratory diseases such as cystic fibrosis, adult and infant respiratory distress syndromes, asthma and emphysema. This paper reviews formulations for delivering therapeutic aerosols to the lungs. Particular emphasis will be placed on preparing fine powders containing macromolecule drugs.

Journal Article↗

PubMed2002

Interactions between bovine beta-lactoglobulin and peptides under different physicochemical conditions.

The aim of this study was to determine if peptides could interact with beta-lactoglobulin (beta-LG) and what the physicochemical conditions promoting their interaction with the protein are. The binding of negatively charged (beta-LG 125-135 and 130-135), positively charged (beta-LG 69-83 and 146-149), and hydrophobic (alphaS1-CN 23-34 and beta-LG 102-105, both bioactive peptides) peptides to bovine beta-LG was determined using an ultrafiltration method under different physicochemical conditions: pH 3.0, 6.8, and 8.0; buffers of 0.05 and 0.1 M; 4, 25, and 40 degrees C; beta-LG/peptide ratios of 1:5 and 1:10. At pH 3.0, none of the peptides interacted with beta-LG at any temperature, buffer molarity, or beta-LG/peptide ratio probably due to electrostatic repulsions between the highly protonated species. At pH 6.8 and 8.0, charged peptides beta-LG 130-135, 69-83, and 146-149 bound to beta-LG under some physicochemical conditions, possibly by nonspecific binding. However, both hydrophobic peptides probably bind to the inner cavity (beta-barrel) of beta-LG, provoking the release of materials absorbing at 214 nm. Given the known biological activities of the hydrophobic peptides used in this study (opioid and ACE-inhibitory activities), their binding to beta-LG may be relevant to a better understanding of the physiological function of the protein.

Amino Acid Sequence↗

PubMed2006

A novel approach based on nanotechnology for investigating the chronic actions of short-lived peptides in specific sites of the brain.

This review presents a novel experimental approach for investigating the chronic actions of short-lived peptides in specific sites of the brain. This method combines the advantages of three different techniques: liposome encapsulation, site-specific microinjection and telemetry. First, liposomes can be designed to remain located at the injection site for a long period of time, where they protect encapsulated peptide from rapid degradation and act as a sustained-release system. Secondly, microinjection allows the administration of peptides in specific sites of the brain with minimal side effects. Finally, using telemetry, it is possible to register physiological parameters and their circadian variations in undisturbed free-moving animals for several days. Angiotensin-(1-7) and angiotensin II were used as peptide models, in order to validate the proposed method. Following the unilateral microinjection of the liposome-encapsulated peptides into the rostral ventrolateral medulla (RVLM) of Wistar rats, long-lasting cardiovascular actions were elicited, for several days. Importantly, new physiological actions of angiotensin-(1-7) at the RVLM were unmasked: modulation of the circadian rhythms of blood pressure and heart rate. It is felt that this method can be applied to a wide variety of short-lived bioactive peptides and should encounter numerous applications in the field of neurosciences.

Angiotensin I↗

PubMed2005

Engineering stable peptide toxins by means of backbone cyclization: stabilization of the alpha-conotoxin MII.

Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the alpha-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.

Animals↗

PubMed2004

Overexpression, purification and characterization of recombinant salmon calcitonin, a therapeutic protein, in Streptomyces avermitilis.

Calcitonin (CT) is a peptide hormone produced by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. Salmon calcitonin (sCT), which is more potent and longer lasting than human CT, has been used widely for the treatment of osteoporosis, paget's disease, hypercalcemic shock and chronic pain in terminal cancer patients. sCT is one of the many bioactive peptides that require C-terminal amidation for full biological activity. In this study we describe the over-expression and over-production of C-terminal amidated sCT in recombinant Streptomyces avermitilis. With this approach the utilization of expensive peptide synthesis can be circumvented.

Amino Acid Sequence↗

PubMed1997

Identification and characterization of a novel human cortistatin-like peptide.

Expressed sequence tags (ESTs) that showed significant homology to rat cortistatin (CST) were found in a human fetal brain cDNA library. A protein coded by the cDNA showed 55% identity to rat preprocortistatin in amino acid. Similarly in the generation of mature peptides from rat preprocortistatin, it was expected that cleavage at dibasic amino acids in the C-terminal portion of the coded protein might produce at least two different sizes of mature peptides with 29 and 17 amino acid residues, respectively. We chemically synthesized the predicted mature peptide with 17 amino acid residues (hCS-17) and examined its biological activities. It bound to all human somatostatin receptor (SSTR) subtypes in almost the same manner as rat CST-14. It also inhibited cAMP production induced by forskolin through SSTRs. Administration of hCS-17 to the cerebral ventricle showed flattening of cortical and hippocampal electroencephalograms in rats. These results indicate that a bioactive peptide encoded by the cDNA is a human counterpart corresponding to rat CST.

Amino Acid Sequence↗

PubMed1982

Chronic intracarotid cannulation of pigeons for administration of behaviorally active peptides.

Chronic intracarotid cannulation of the common carotid artery was performed in the pigeon. The catheter system of polyethylene tubing consisted of an indwelling component and an injection component. The indwelling component was exteriorized at the occiput so the bird could not reach the catheter with its beak. Following surgery, the pigeons were housed individually and received food and water ad libitum and no special care was necessary. The catheter was flushed daily with heparin in 0.9% NaCl solution to maintain patency. 30 pigeons were continuously or intermittently infused with bioactive peptides for up to 60 days after cannulation.

Animals↗

PubMed1990

Biosynthetic response of mouse intermediate pituitary gland to induced drinking and dehydration.

There are indications that the intermediate lobe peptide alpha-MSH is involved in the regulation of the hydromineral balance in mice and other mammals. The purpose of our studies was to determine whether manipulation of this balance in the mouse could lead to changes in either the rate of POMC biosynthesis in the pars intermedia or to changes in the direction of the processing of the precursor protein to form bioactive peptides. The results show that excess drinking, induced by substitution of drinking water by a 5% glucose solution, causes a rapid increase in POMC synthesis, whereas dehydration has the opposite effect; no evidence could be found that the above treatments have any effect on the processing of POMC, although strain differences were found in level of N-terminal acetylation of newly synthesized melanotropins and endorphins. The changes in various parameters of the hydromineral balance of the animals are consistent with the concept that peptides of the pars intermedia may be involved in regulating plasma aldosterone levels under severe conditions of low plasma sodium concentration.

Animals↗

PubMed2004

Solution structure of the cyclotide palicourein: implications for the development of a pharmaceutical framework.

The cyclotides are a family of disulfide-rich proteins from plants. They have the characteristic structural features of a circular protein backbone and a knotted arrangement of disulfide bonds. Structural and biochemical studies of the cyclotides suggest that their unique physiological stability can be loaned to bioactive peptide fragments for pharmaceutical and agricultural development. In particular, the cyclotides incorporate a number of solvent-exposed loops that are potentially suitable for epitope grafting applications. Here, we determine the structure of the largest known cyclotide, palicourein, which has an atypical size and composition within one of the surface-exposed loops. The structural data show that an increase in size of a palicourein loop does not perturb the core fold, to which the thermodynamic and chemical stability has been attributed. The cyclotide core fold, thus, can in principle be used as a framework for the development of useful pharmaceutical and agricultural bioactivities.

Amino Acid Sequence↗

PubMed2002

Synthesis, conformational analysis, and spectroscopic characterization of peptides based on Daf, the first rigid transition-metal receptor, cyclic C(alpha,alpha)-disubstituted glycine.

Three series of terminally protected model oligopeptides to the nonamer level, based on 9-amino-4,5-diazafluorene-9-carboxylic acid, the first rigid bipyridine-type C(alpha,alpha)-disubstituted glycine, and either Gly, L-Ala, or Aib residues were synthesized by solution methods and fully characterized. The molecular structures of two derivatives and one tripeptide were determined in the crystal state by x-ray diffraction. Moreover, the solution preferred conformations of these peptides were assessed by Fourier transform infrared absorption and (1)H-NMR techniques. A comparison with the known structural tendencies of the strictly related C(alpha,alpha)-disubstituted glycyl residues 1-aminocyclopentane-1-carboxylic acid and 9-aminofluorene-9-carboxylic acid is made, and the implications for the use of the 9-amino-4,5-diazafluorene-9-carboxylic acid residue in conformationally constrained analogs of bioactive peptides are briefly examined. A spectroscopic (uv absorption, fluorescence, CD) characterization of this novel heteroaromatic C(alpha,alpha)-disubstituted glycine is also reported. Finally, preliminary conformational data and membrane activity measurements are discussed for an analog of the lipopeptaibol antibiotic [L-Leu(11)-OMe] trichogin GA IV in which a 9-amino-4,5-diazafluorene-9-carboxylic acid residue was synthetically incorporated in position 1 (replacing the original Aib residue).

Aza Compounds↗

PubMed1986

Thyrotropin-releasing hormone precursor: characterization in rat brain.

To characterize the precursor of mammalian thyrotropin-releasing hormone (TRH), a rat hypothalamic lambda gt11 library was screened with an antiserum directed against a synthetic peptide representing a portion of the rat TRH prohormone. The nucleotide sequence of the immunopositive complementary DNA encoded a protein with a molecular weight of 29,247. This protein contained five copies of the sequence Gln-His-Pro-Gly flanked by paired basic amino acids and could therefore generate five TRH molecules. In addition, potential cleavage sites in the TRH precursor could produce other non-TRH peptides, which may be secreted. In situ hybridization to rat brain sections demonstrated that the pre-proTRH complementary DNA detected neurons concentrated in the parvocellular division of the paraventricular nucleus, the same location as cells detected by immunohistochemistry. These findings indicate that mammalian TRH arises by posttranslational processing of a larger precursor protein. The ability of the TRH prohormone to generate multiple copies of the bioactive peptide may be an important mechanism in the amplification of hormone production.

Amino Acid Sequence↗

PubMed2003

Angiotensin I-converting-enzyme-inhibitory and antibacterial peptides from Lactobacillus helveticus PR4 proteinase-hydrolyzed caseins of milk from six species.

Sodium caseinates prepared from bovine, sheep, goat, pig, buffalo or human milk were hydrolyzed by a partially purified proteinase of Lactobacillus helveticus PR4. Peptides in each hydrolysate were fractionated by reversed-phase fast-protein liquid chromatography. The fractions which showed the highest angiotensin I-converting-enzyme (ACE)-inhibitory or antibacterial activity were sequenced by mass spectrum and Edman degradation analyses. Various ACE-inhibitory peptides were found in the hydrolysates: the bovine alpha(S1)-casein (alpha(S1)-CN) 24-47 fragment (f24-47), f169-193, and beta-CN f58-76; ovine alpha(S1)-CN f1-6 and alpha(S2)-CN f182-185 and f186-188; caprine beta-CN f58-65 and alpha(S2)-CN f182-187; buffalo beta-CN f58-66; and a mixture of three tripeptides originating from human beta-CN. A mixture of peptides with a C-terminal sequence, Pro-Gly-Pro, was found in the most active fraction of the pig sodium caseinate hydrolysate. The highest ACE-inhibitory activity of some peptides corresponded to the concentration of the ACE inhibitor (S)-N-(1-[ethoxycarbonyl]-3-phenylpropyl)-ala-pro maleate (enalapril) of 49.253 micro g/ml (100 micro mol/liter). Several of the above sequences had features in common with other ACE-inhibitory peptides reported in the literature. The 50% inhibitory concentration (IC(50)) of some of the crude peptide fractions was very low (16 to 100 micro g/ml). Some identified peptides were chemically synthesized, and the ACE-inhibitory activity and IC(50)s were confirmed. An antibacterial peptide corresponding to beta-CN f184-210 was identified in human sodium caseinate hydrolysate. It showed a very large spectrum of inhibition against gram-positive and -negative bacteria, including species of potential clinical interest, such as Enterococcus faecium, Bacillus megaterium, Escherichia coli, Listeria innocua, Salmonella spp., Yersinia enterocolitica, and Staphylococcus aureus. The MIC for E. coli F19 was ca. 50 micro g/ml. Once generated, the bioactive peptides were resistant to further degradation by proteinase of L. helveticus PR4 or by trypsin and chymotrypsin.

Amino Acid Sequence↗

PubMed2005

Overexpression and purification of recombinant eel calcitonin and its phylogenetic analysis.

Calcitonin (CT), a peptide hormone that is widely used for the treatment of osteoporosis, Paget's disease, hypercalcemic shock and chronic pain in terminal cancer patients, is produced by the para-follicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. Fish calcitonin, like eel calcitonin (eCT), is more potent and longer lasting than human CT and is one of the many bioactive peptides that require C-terminal amidation for full biological activity. In this study we describe the over-expression and over-production of C-terminal amidated eCT in recombinant Streptomyces avermitilis. A phylogenetic analysis was performed with all the known CT amino acid sequences.

Amino Acid Sequence↗

PubMed2001

Expression of adrenomedullin and peptide amidation activity in human prostate cancer and in human prostate cancer cell lines.

After therapeutic hormone deprivation, prostate cancer (CaP) cells often develop androgen-independent growth through not-well-defined mechanisms. The presence of neuroendocrine (NE) cells is often greater in prostate carcinoma than in normal prostate, and the frequency of NE cells correlates with tumor malignancy, loss of androgen sensitivity, increase of autocrine-paracrine activity, and poor prognosis. In some CaPs, neuropeptides have been previously implicated as growth factors. Peptidylglycine alpha-amidating monooxygenase (PAM) is the enzyme producing alpha-amidated bioactive peptides from their inactive glycine-extended precursors. In the present work, we demonstrate that androgen-independent PC-3 and DU145 cell lines, derived from human CaP, express PAM in vitro and in xenografts implanted in athymic nude mice, indicating that they are able to produce alpha-amidated peptides. Contrarily, barely detectable levels of PAM were found in the androgen-sensitive LNCaP cell line. We also show that whereas PC-3 and DU145 cells produce and secrete adrenomedullin (AM), a multifunctional amidated peptide, no expression was found in LNCaP cells. We further demonstrate that AM acts as a growth factor for DU145 cells, which suggests the existence of an autocrine loop mechanism that could potentially drive neoplastic growth. PAM mRNA levels were found to be 3-fold higher in prostate adenocarcinomas compared with that of human benign prostate hyperplasia (BPH) as demonstrated by real-time quantitative reverse transcription-PCR. The analysis of AM message expression in BPH and CaP (Gleason's score, 6-9) shows a clear distinction between benign and CaP. The expression was detected only in adenocarcinomas tissues with a marked increase in samples with a high Gleason's score. Immunocytochemically, AM was localized in the carcinomatous epithelial compartment. NE phenotype, assessed after the immunocytochemical localization of neuron-specific enolase (NSE), was found in both the epithelial and the stromal compartments of cancers; in BPH, only some spare basal cells were NSE-labeled. Cancer progression could be accelerated by peptides secreted by a population of cells capable of inducing androgen-independent tumoral growth via autocrine-paracrine mechanisms.

Adenocarcinoma↗

PubMed2002

Aminopeptidases in Caenorhabditis elegans and Panagrellus redivivus: detection using peptide and non-peptide substrates.

Aminopeptidase activities were detected in extracts of the free-living nematodes Caenorhabditis elegans and Panagrellus redivivus using the aminoacyl substrate L-alanine-4-nitroanilide. The activities exhibited similarities in Km (C. elegans = 2.22 mM; P. redivivus = 2.09 mM) and specific activity (C. elegans = 1.38 +/- 0.43 mAU min(-1) x g(-1); P. redivivus, 1.23 +/- 0.18m AU min(-1) microg(-1). Each is inhibited competitively by amastatin (C. elegans IC50 = 0.46 microM; P. redivivus IC50 = 15.90 microM) and non-competitively by leuhistin (C. elegans IC50 = 3.00 microM; P. redivivus IC50 = 37.35 microM). The bioactive peptides adipokinetic hormone and substance P decrease the apparent aminopeptidase activities of each extract suggesting that the peptides compete with the Ala-pNA as substrates. With each extract, adipokinetic hormone appeared to be the more effective substrate. Digestion of adipokinetic hormone by C. elegans and P. redivivus extracts in the presence and absence of 1 mM amastatin produced distinct chromatographic profiles that suggest different digestion patterns for the two species. However, amastatin had clear effects on chromatographic profiles from each species indicating that an aminopeptidase is involved in the digestion of the peptide substrates. The data presented indicate that extracts of free-living nematodes are capable of metabolizing peptide hormones, and that this metabolism involves substrate-selective aminopeptidases.

Amino Acids↗