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At least 1,117 records · Page 62Linked to original sources
PubMed2004

Detecting bioactive amyloid beta peptide species in Alzheimer's disease.

Amyloid beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of A beta that induces neurodegeneration in AD, defined here as bioactive A beta, is not clear. Preventing the formation of bioactive A beta or inactivating previously formed bioactive A beta should be a promising approach to treat AD. We have previously developed a cell-based assay for the detection of bioactive A beta species. The assay is based upon the correlation between the ability of an A beta sample to induce a unique form of cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] formazan exocytosis, and its ability to activate glia and induce neurotoxicity. Here, we show that this cell-based assay is not only useful for a cellular model of A beta amyloidogenesis but is also able to detect bioactive A beta species in a transgenic mouse model of AD, as well as in post-mortem cortex samples from AD patients. There is a good correlation between the extent of glia activation and the level of bioactive A beta species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive A beta species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD.

Age Factors↗
PubMed2002

Influence of silaproline on peptide conformation and bioactivity.

The analogue gamma-(dimethylsila)-proline, denoted silaproline (Sip), was synthesized in both enantiomerically pure forms by diastereoselective alkylation of a chiral glycine equivalent with use of Schöllkopf's bis-lactim ether method. The effect of replacing a proline residue in model peptides by this new proline surrogate has been examined in the crystal state by X-ray diffraction and in solution by IR absorption and NMR techniques. Silaproline and proline-containing sequences exhibit very similar conformational properties. Silaproline was also substituted for proline in a neurotensin (8-13) analogue that retained biological activity and exhibited enhanced resistance to biodegradation.

Animals↗
PubMed2006

Treating Alzheimer's disease by inactivating bioactive amyloid beta peptide.

Treating Alzheimer's disease (AD) is one of today's biggest unmet medical needs. The drugs currently available transiently relieve some symptoms but have no significant effects on the progression of the disease. Progress in the past decade suggests that the amyloidogenesis of the inactive monomeric amyloid beta peptide (Abeta) into a subset of toxic Abeta polymers is responsible for neurodegeneration in AD. Not all forms of Abeta aggregates are damaging, for there are patients whose brains accumulated large amounts of Abeta in the form of plaques, but they had no obvious neurodegeneration and symptoms of dementia. Since Abeta can polymerize into many types of polymers or aggregates, the form of Abeta that induces neurodegeneration in AD, defined here as bioactive Abeta, is not clear. Preventing the formation of bioactive Abeta or inactivating previously formed bioactive Abeta is a promising approach for treating AD. This review describes our efforts to develop a cell-based assay for detecting bioactive Abeta, to verify the concept of bioactive Abeta in an animal model of AD and in post mortem brain tissue from AD patients, and to use this assay to screen for drugs that can inactivate bioactive Abeta. These studies show the proof in principle that inactivating bioactive Abeta is a promising approach to treat AD. Several promising compounds that can inactivate bioactive Abeta species are also described.

Alzheimer Disease↗
PubMed2003

Use of intein-directed peptide biosynthesis to improve serum stability and bioactivity of a gelatinase inhibitory peptide.

Screening of phage display libraries allows rapid identification of peptides binding to a target. However, functional analysis of the phage sequences and their reproduction as soluble and stable peptides are often the most time-consuming part in the screening. We have used here intein-based peptide biosynthesis to produce a phage-display derived gelatinase inhibitory peptide CTTHWGFTLC and to identify the critical residues for gelatinase inhibitory activity by performing alanine-scanning mutagenesis. By biosynthetic incorporation of 5-fluorotryptophan, we obtained an inhibitor of MMP-2 and MMP-9 gelatinases that showed a 6-fold enhancement in serum stability in comparison to the wild-type peptide. The new peptide also had an improved ability to inhibit tumor cell migration. These studies indicate the utility of intein methodology for synthesis and design of peptides obtained by phage display.

Alanine↗
PubMed1991

Antiserum to an inhibin alpha-chain peptide neutralizes inhibin bioactivity and increases ovulation rate in sheep.

A synthetic fragment representing the N-terminal 25 amino acid residues of the alpha-subunit of ovine inhibin (alpha-IF) was coupled to human alpha-globulin (h alpha-G) and used as an antigen. In Exp. 1, ovine antiserum generated against alpha-IF-h alpha-G was shown in vitro to neutralize inhibin bioactivity contained in ovine follicular fluid. In Exp. 2, 18 lambs were immunized with .3, .6 and 1.2 mg alpha-IF-h alpha-G or equivalent doses of h alpha-G. Antibody titer to alpha-IF was detected only in serum from lambs immunized against alpha-IF-h alpha-G and was first detected 27 +/- 2 d after primary immunization. Thereafter, antibody titers increased steadily. The degree of antibody responses was unrelated to antigen dose and differed among lambs. Plasma FSH concentrations were unchanged, whereas LH concentrations were lower (P less than .001) in sheep immunized against alpha-IF-h alpha-G. Ovulation rate was increased (3.5 +/- .5 vs 1.5 +/- .1; P less than .01) in lambs immunized against alpha-IF-h alpha-G. Ovulation rate was similar among animals receiving different antigen doses and increased with time after primary immunization (P less than .01). At estrous periods occurring approximately 34, 50, 74 and 107 d after primary immunization, respective ovulation rates were 157, 169, 207 and 450% of control values. Ovulation rate and antibody titer were correlated positively (pooled r = .95; P less than .01) within lambs. In Exp. 3, three lambs were immunized with .25 mg unconjugated alpha-IF; this was nonantigenic. In conclusion, the use of a synthetic fragment of the alpha-subunit of ovine inhibin as a hapten elicits an antibody capable of neutralizing inhibin bioactivity in vitro and increasing ovulation rate in vivo.

Alpha-Globulins↗
PubMed1996

Truncation studies of alpha-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity.

Truncation studies of alpha-melanotropin peptides identify tripeptide analogues exhibiting prolonged agonist bioactivity: PEPTIDES 17(6) 995-1002, 1996.-Systematic analysis of fragment derivatives of the superpotent alpha-MSH analogue. Ac-Ser.Tyr-Ser-Nle4-Glu- His-DPhe7-Arg-Trp-Gly-Lys-Pro-Val-NH2(NDP-MSH), led to the discovery of tripeptide agonists possessing prolonged bioactivity in the frog skin assay. Of particular significance to this discovery was Ac-DPhe-Arg-DTrp-NH2, which was the most potent tripeptide in this series exhibiting sustained melanotropic activity. Different pharmacophore models appear to exist that are dependent on the substructure and stereochemistry of the MSH(6-9) "active site." The tripeptides Ac-DPhe-Arg-Trp-NH2, Ac-DPhe-Arg-DTrp-NH2, and Ac-DPhe-DArg-Trp-NH2 stereo-chemical combinations require only Phe7-Xaa8-Trp9, whereas Ac-DPhe-DArg-DTrp-NH2, Ac-Phe-Arg-DTrp-NH2, and Ac-Phe-Arg-Trp-NH2 additionally require His4 for minimal biological activity. Ac-DPhe-Arg-DTrp-NH2 represents a novel prototype lead for the development of MSH-based peptidomimetic agonists.

Amino Acid Sequence↗
PubMed2002

Synthesis of RGD containing peptides and their bioactivities.

RGDS, RGDV, and RGDF were used for the structural modification of YIGSR and YIGSK, the sequences involved in the development of metastasis disease. By use of a solution method, YIGSRRGDS, YIGSRRGDV, YIGSRRGDF, YIGSKRGDS, YIGSKRGDV, YIGSKRGDF, YIGSRYIGSK, and YIGSKYIGSR were prepared in good yield. The results of bioassay in vitro indicated that the target property of RGDS, RGDV, and RGDF to high affinity-receptors may be responsible for the enhanced anti-aggregation, anti-adhesion, and anti-invasion potency.

Blood Platelets↗
PubMed1999

psi(SO2NH) transition state isosteres of peptides. Synthesis and bioactivity of sulfonamido pseudopeptides related to carnosine.

This paper reports the synthesis of tauryl dipeptides related to carnosine. In particular H-Tau-His-OH (5), H-Tau-His(pi-Me)-OH (6) and H-Tau-His(tau-Me)-OH (9) are described. The enzyme carnosinase has been isolated from pig kidney and after purification has been used to test the stability and the inhibitory activity of the three new analogues. H-Tau-His-OH (5) and H-Tau-His(tau-Me)-OH (9) were found to possess weak inhibitory properties towards carnosinase, while H-Tau-His(pi-Me)-OH (6) proved to be devoid of any significant activity. All the three sulfonamido pseudopeptides 5, 6 and 9 show stability to carnosinase activity.

Carnosine↗
PubMed1998

Chronic infusions of brain natriuretic peptide in conscious sheep: bioactivity at low physiological levels.

1. The circulating cardiac hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have similar bioactivity, as judged by comparative short-term studies. However, no study has reported the effects of longer-term administration of BNP. Accordingly, we have compared the haemodynamic, hormonal and renal actions of chronic (4-day) administration of BNP and ANP (0.5 pmol. min-1.kg-1) in a vehicle-controlled study in normal conscious sheep. 2.BNP infusions raised plasma BNP levels within the physiological range (4 pmol/l increment, P<0.001) and increased cyclic GMP levels (P=0.01). BNP infusions induced significant falls in right atrial pressure (P=0.048), stroke volume (P=0.014) and cardiac output (P=0. 003) associated with a rise in haematocrit (P=0.001). There were no significant renal effects or changes in renin-aldosterone. By comparison, equimolar infusion of ANP induced a smaller increment in plasma ANP levels (2 pmol/l, P=0.03) with qualitatively similar but statistically non-significant changes in plasma cyclic GMP and haemodynamic indices.3.In conclusion, chronic low-dose infusions of BNP elevate plasma cyclic GMP levels and induce significant haemodynamic actions. This study provides evidence that subtle variations in circulating BNP levels, well within the physiological range, may be important in long-term cardiovascular control.

Analysis of Variance↗
PubMed2003

Synthetic peptides in the form of dendrimers become resistant to protease activity.

In previous papers, we observed that dendrimers of peptide mimotopes of the nicotinic receptor ligand site are strong antidotes against the lethality of the nicotinic receptor ligand alpha-bungarotoxin. Although their in vitro activity is identical to that of dendrimers, the corresponding monomeric peptide mimotopes are not effective in vivo. Because the higher in vivo efficiency of dendrimers could not in this case be related to polyvalent interaction, the stability to blood protease activity of monomeric versus tetrabranched dendrimeric mimotope peptides was compared here by incubating three different mimotopes with human plasma and serum. Unmodified peptides and cleaved sequences were followed by high pressure liquid chromatography and mass spectrometry. Tetrabranched peptides were shown to be much more stable in plasma and also in serum. To assess the notable stability of multimeric peptides, different bioactive neuropeptides, including enkephalins, neurotensin and nociceptin, were synthesized in monomeric and tetrabranched forms and incubated with human plasma and serum and with rat brain membrane extracts. All the tetrabranched neuropeptides fully retained biological activity and generally showed much greater stability to blood and brain protease activity. Some tetrabranched peptides were also resistant to trypsin and chymotrypsin. Our findings provide new insights into the possible therapeutic use of bioactive peptides.

Animals↗
PubMed2002

Mimetics of the peptide beta-strand.

Bioactive structures of peptides represent important clues for drug discovery and development although peptides themselves have substantial limitations as drugs. One promising approach to overcoming the limitations of peptides is to progressively replace amide bonds in peptides with non-peptidic constraints that bring drug-like properties like stability and bioavailability to the molecules. These constraints can also be used to mould molecules into shapes which mimic key elements of protein secondary structure that confer bioactivity to protein surfaces. Preorganizing a molecule into the shape recognized by a receptor results in high affinity binding though a considerable entropy saving and is an effective approach to engineering highly bioactive drug leads. One peptide structure, the extended beta strand, has only recently been identified as a fundamental recognition element in physiological processes. Relatively few molecules have been described as constrained mimics of extended peptide conformations. We now summarize some approaches to mimicking peptide beta strands, and illustrate these with examples of bioactive, stable and bioavailable molecules that are conformationally biased to mimic the extended peptide beta strand.

Anti-Bacterial Agents↗
PubMed1989

Cholecystokinin, gastrin and their precursors in pheochromocytomas.

Using sequence-specific radioimmunoassays before and after cleavage with trypsin and carboxypeptidase B, we have examined the occurrence and molecular nature of cholecystokinin (CCK) and gastrin peptides in bioactive (i.e. alpha-carboxyamidated) as well as non-amidated precursor forms in extracts from 13 human pheochromocytomas. All but one tumour contained amidated CCK, but only in moderate amounts (less than or equal to 20 pmol/g tissue). In contrast to the complete sulphation in tissues which normally produce CCK (the brain and small intestine), the amidated adrenal CCK peptides were poorly sulphated (less than or equal to 17%). Four pheochromocytomas, including the one without amidated CCK, contained between 28 and 0.2 pmol amidated gastrin/g, mainly in the form of sulphated gastrin-17. In addition, all tumours contained biosynthetic precursors of both CCK and gastrin. In most extracts there was more precursor than bioactive peptide(s), the progastrin concentration ranging up to 338 pmol/g. The results show that pheochromocytomas synthesize CCK and gastrin. The posttranslational processing differs, however, markedly from that of the principal CCK and gastrin producing tissues, with respect to both proteolytic cleavages and amino acid derivatization. This emphasizes that accurate quantitation in tumours requires assays which measure the translation products irrespective of their degree of processing.

Adrenal Gland Neoplasms↗
PubMed2003

The renin-angiotensin and the kallikrein-kinin systems.

The renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS) each encompasses a large number of molecules, with several participating in both systems. The RAS generates a family of bioactive angiotensin peptides with varying biological activities. These include angiotensin-(1-8) (Ang II), angiotensin-(2-8) (Ang III), angiotensin-(3-8) (Ang IV), and angiotensin-(1-7) [Ang-(1-7)]. Ang II and Ang III act on type 1 (AT(1)) and type 2 (AT(2)) angiotensin receptors, whereas, Ang IV and Ang-(1-7) act on their own receptors. The KKS also generates a family of bioactive peptides with varying biological activities. These include hydroxylated and non-hydroxylated bradykinin and kallidin peptides and their carboxypeptidase metabolites des-Arg(9)-bradykinin and des-Arg(10)-kallidin. Whereas bradykinin and kallidin act mainly via the type 2 bradykinin (B(2)) receptor, des-Arg(9)-bradykinin and des-Arg(10)-kallidin act mainly via the type 1 bradykinin (B(1)) receptor. The AT(1) receptor forms heterodimers with the AT(2) and B(2) receptors and there is cross talk between the AT(1) and epidermal growth factor receptors. The B(2) receptor also interacts with angiotensin converting enzyme and nitric oxide synthase. Both angiotensin and kinin peptides are metabolised by many different peptidases that are important determinants of the activities of the RAS and KKS, and several of which participate in both systems.

Angiotensinogen↗
PubMed2005

Influence of TAT-peptide polymerization on properties and transfection activity of TAT/DNA polyplexes.

Use of bioactive cationic peptides as gene carriers is limited by instability of their DNA complexes in vivo and by the loss of their biological activity due to undesired interactions of their bioactive parts with the DNA. To overcome the two major limitations, biodegradable high-molecular-weight form of TAT peptide (POLYTAT) sensitive to cellular redox-potential gradients was synthesized in this study by oxidative polycondensation. Physicochemical and transfection properties of DNA polyplexes based on POLYTAT were investigated and compared with polyplexes based on TAT polymer prepared by in situ template-assisted polymerization. Physicochemical properties of TAT-based polyplexes were affected by the molecular weight and method of polymerization of the TAT peptide. All TAT-based DNA polyplexes exhibited reduced cytotoxicity when compared with control polyethylenimine (PEI) polyplexes. Polyplexes based on both high-molecular-weight TAT polypeptides exhibited increased transfection efficiency compared to control TAT peptide but lower than that of PEI polyplexes. The evidence shows that transfection activity of TAT-based polyplexes is strongly dependent on the presence of chloroquine and therefore suggests that TAT polyplexes are internalized by an endocytosis. Overall, high-molecular-weight reducible polycations based on bioactive peptides has the potential as versatile carriers of nucleic acids that display low cytotoxicity and can prove to be especially beneficial in cases that require surface presentation of membrane-active or cell-specific targeting peptides.

Animals↗
PubMed2006

Ligand profiling and identification technology for searching bioactive ligands.

We introduce a new methodology named ligand profiling and identification for effective discovery of bioactive ligands such as peptide hormones. This technology was developed from a new concept of parallel column chromatography and active fraction profiling by nano-LC MS. Traditional methods use sequential column chromatography, and thus are inevitably limited by the low abundance of the peptide of interest and by a low yield due to the many column steps. Using this new technology, insulin was successfully identified and diarginylinsulin, a minor intermediate form of insulin, was unexpectedly also identified simultaneously from 100 mg of porcine pancreatic tissue. This integrative technology could be used to search for various low-abundance peptides (or bioactive molecules) rapidly and simultaneously, by applying this to the later stages of traditional sequential purification.

Animals↗
PubMed2026

Comparative characterization of six teleost piscidins reveals distinct antimicrobial, antibiofilm and stability profiles.

Piscidins are cationic &#x3b1;-helical antimicrobial peptides (AMPs) that constitute a key component of the innate immune defense of teleost fish, yet the relationship between their genomic organization, structural properties, and functional specialization remains incompletely understood. In this study, six piscidin peptides from Epinephelus akaara, Seriola dumerili, Thunnus maccoyii, Argyrosomus regius, Dicentrarchus labrax, and Epinephelus coioides were characterized through an integrated sequence-to-function approach combining comparative genomics, structural modeling, physicochemical analysis, and in vitro validation, with the aim of identifying candidates with potential for biomedical and biotechnological applications. All genes studied exhibited the conserved four-exon, three-intron architecture characteristic of teleost piscidins. Structural modeling and circular dichroism confirmed &#x3b1;-helical conformations under membrane-mimetic conditions, despite measurable differences in hydrophobicity, charge distribution, and predicted membrane insertion parameters. Antimicrobial assays revealed distinct functional profiles: Sd_FI25 and Epinecidin_1 displayed broad antibacterial activity against Gram-positive and Gram-negative pathogens, whereas Dl_FI22 showed selective activity with reduced temporal persistence associated with lower peptide stability. Ea_FF25 exhibited comparatively weak antibacterial potency. Antibiofilm activity varied among peptides and did not uniformly parallel planktonic MIC values. Computational predictions further suggested antiviral and antitumoral potential for several sequences, extending their prospective relevance beyond classical antibacterial roles. Conserved genomic architecture and &#x3b1;-helical structure coexist with pronounced functional diversification among teleost piscidins. These findings demonstrate that integrating structural prediction with experimental validation is an effective strategy for identifying fish-derived innate immune peptides as candidates for biomedical applications.

Antimicrobial activity↗