| 17550431 |
Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata |
10.1111/j.1365-2915.2007.00668.x. |
Med Vet Entomol |
Antibacterial substances of low molecular weight isolated from the blowfly, Lucilia sericata
Abstract
- Low molecular weight compounds were isolated by high-performance liquid chromatography from the maggot or haemolymph extracts of Lucilia sericata (Meigen) (Diptera: Calliphoridae). Using gas chromatography-mass spectrometry analysis, three compounds were obtained: p-hydroxybenzoic acid (molecular weight 138 Da), p-hydroxyphenylacetic acid (molecular weight 152 Da) and octahydro-dipyrrolo[1,2-a;1',2'-d] pyrazine-5,10-dione (molecular weight 194 Da), also known as the cyclic dimer of proline (or proline diketopiperazine or cyclo[Pro,Pro]). All three molecules revealed antibacterial activity when tested against Micrococcus luteus and/or Pseudomonas aeruginosa, and the effect was even more pronounced when these molecules were tested in combination and caused lysis of these bacteria.
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| 17551641 |
Design and synthesis of all diastereomers of cyclic pseudo-dipeptides as mimics of cyclic CXCR4 pentapeptide antagonists |
10.1039/b702649h. |
Org Biomol Chem |
Design and synthesis of all diastereomers of cyclic pseudo-dipeptides as mimics of cyclic CXCR4 pentapeptide antagonists
Abstract
- The four diastereomers of 2,5-bis[(3-guanidino)propyl]-1-[3-(4-hydroxyphenyl)propionyl]-7-(2-naphthylacetyl)-1,4,7-triazacycloundec-9-en-3-one (-) and of 2,5-bis[(3-guanidino)propyl]-1-(4-hydroxyphenylacetyl)-7-(2-naphthylacetyl)-1,4,7-triazacycloundec-9-en-3-one (-) were synthesized by a divergent methodology from l- and D-glutamic acids. The 11-membered ring core was made by ring closing metathesis of linear bis(allylamines), and the guanidyl functions were introduced by a simultaneous double Mitsunobu reaction using bis(Boc)guanidine. These compounds were designed to mimic cyclic pentapeptide FC131 (c[Gly-D-Tyr-Arg-Arg-Nal]).
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| 17553876 |
The amino terminus of varicella-zoster virus (VZV) glycoprotein E is required for binding to insulin-degrading enzyme, a VZV receptor. |
10.1128/jvi.00286-07 |
J. Virol. |
The amino terminus of varicella-zoster virus (VZV) glycoprotein E is required for binding to insulin-degrading enzyme, a VZV receptor.
Abstract
- Varicella-zoster virus (VZV) glycoprotein E (gE) is required for VZV infection. Although gE is well conserved among alphaherpesviruses, the amino terminus of VZV gE is unique. Previously, we showed that gE interacts with insulin-degrading enzyme (IDE) and facilitates VZV infection and cell-to-cell spread of the virus. Here we define the region of VZV gE required to bind IDE. Deletion of amino acids 32 to 71 of gE, located immediately after the predicted signal peptide, resulted in loss of the ability of gE to bind IDE. A synthetic peptide corresponding to amino acids 24 to 50 of gE blocked its interaction with IDE in a concentration-dependent manner. However, a chimeric gE in which amino acids 1 to 71 of VZV gE were fused to amino acids 30 to 545 of herpes simplex virus type 2 gE did not show an increased level of binding to IDE compared with that of full-length HSV gE. Thus, amino acids 24 to 71 of gE are required for IDE binding, and the secondary structure of gE is critical for the interaction. VZV gE also forms a heterodimer with glycoprotein gI. Deletion of amino acids 163 to 208 of gE severely reduced its ability to form a complex with gI. The amino portion of IDE, as well an IDE mutant in the catalytic domain of the protein, bound to gE. Therefore, distinct motifs of VZV gE are important for binding to IDE or to gI.
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| 17570159 |
Barusiban suppresses oxytocin-induced preterm labour in non-human primates |
10.1186/1471-2393-7-S1-S15. |
BMC Pregnancy Childbirth |
Barusiban suppresses oxytocin-induced preterm labour in non-human primates
Abstract
- Preterm labour (PTL) is a major cause of neonatal mortality and morbidity, and oxytocin (OT) antagonists are potential tocolytics. Atosiban (TRACTOCILE) is a mixed vasopressin V1A/OT antagonist registered for acute treatment of PTL in Europe. Other off-label drugs have serious side effects. Barusiban is a selective OT antagonist which has reached clinical development. A monkey model with OT-induced PTL was developed to compare barusiban and atosiban. In addition, the feasibility for long-term treatment of PTL with barusiban was explored.
Conscious pregnant cynomolgus monkeys were monitored for intrauterine pressure (IUP). A sensor for IUP was implanted into the amniotic cavity, and biopotential sensors for electromyogram were attached to the uterus. For short-term experiments, individual low-dose OT infusions induced stable submaximal uterine contractions. Barusiban and atosiban were administered either as intravenous bolus or infusion at high or low doses. For long-term treatment, low-dose OT was infused daily for 3-6 hours to mimic PTL. In addition, continuous high-dose infusions of barusiban (150 microg kg-1 h-1) or fenoterol (3 microg kg-1 h-1) were administered.
Contractions of 15-40 mmHg were induced with individual OT infusions at 5-90 mU kg-1 h-1, and no OT-related desensitization occurred. Correlation was demonstrated between electromyograms and IUP curves. Barusiban was well tolerated and its potency was 4 times higher than atosiban's. Barusiban and atosiban demonstrated >95% efficacy. However, barusiban's duration of action was >13 hours (atosiban's 1-3 hours) and reversible with high-dose OT in emergency situations. OT control and fenoterol-treated monkeys delivered preterm (ca. day 154) and showed an increase in overall IUP. Barusiban-treated animals delivered normally following end of treatment (ca. day 163).
The presented telemetry model provides an excellent method to evaluate PTL drug candidates. OT induced stable repetitive contractions and no desensitisation. Barusiban and atosiban demonstrated high efficacy and rapid onset of action. Barusiban, a selective OT antagonist has higher potency and prolonged duration of action than atosiban. Barusiban effectively suppressed IUP during daily OT-challenges, delayed labour, and prolonged monkeys' pregnancy till term.
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| 17583734 |
Crystallographic structure of the human leukocyte antigen DRA, DRB3*0101: models of a directional alloimmune response and autoimmunity |
10.1016/j.jmb.2007.05.025. |
J Mol Biol |
Crystallographic structure of the human leukocyte antigen DRA, DRB3*0101: models of a directional alloimmune response and autoimmunity
Abstract
- We describe structural studies of the human leukocyte antigen DR52a, HLA-DRA/DRB3*0101, in complex with an N-terminal human platelet integrin alphaII(B)betaIII glycoprotein peptide which contains a Leu/Pro dimorphism. The 33:Leu dimorphism is the epitope for the T cell directed response in neonatal alloimmune thrombocytopenia and post-transfusion purpura in individuals with the alphaII(B)betaIII 33:Pro allele, and defines the unidirectional alloimmune response. This condition is always associated with DR52a. The crystallographic structure has been refined to 2.25 A. There are two alphabeta heterodimers to the asymmetric unit in space group P4(1)2(1)2. The molecule is characterized by two prominent hydrophobic pockets at either end of the peptide binding cleft and a deep, narrower and highly charged P4 opening underneath the beta 1 chain. Further, the peptide in the second molecule displays a sharp upward turn after pocket P9. The structure reveals the role of pockets and the distinctive basic P4 pocket, shared by DR52a and DR3, in selecting their respective binding peptide repertoire. We observe an interesting switch in a residue from the canonically assigned pocket 6 seen in prior class II structures to pocket 4. This occludes the P6 pocket helping to explain the distinctive "1-4-9" peptide binding motif. A beta57 Asp-->Val substitution abrogates the salt-bridge to alpha76 Arg and along with a hydrophobic beta37 is important in shaping the P9 pocket. DRB3*0101 and DRB1*0301 belong to an ancestral haplotype and are associated with many autoimmune diseases linked to antigen presentation, but whereas DR3 is susceptible to type 1 diabetes DR52a is not. This dichotomy is explored for clues to the disease.
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| 17585874 |
Recombinant expression, synthesis, purification, and solution structure of arenicin |
10.1016/j.bbrc.2007.06.029. |
Biochem Biophys Res Commun |
Recombinant expression, synthesis, purification, and solution structure of arenicin
Abstract
- Arenicins are 21-residue cationic antimicrobial peptides, isolated from marine polychaeta Arenicola marina. In order to determine a high-resolution three-dimensional structure of arenicin-2, the recombinant peptide was overexpressed as a fused form in Escherichia coli. Both arenicin isoforms were synthesized using the Fmoc-based solid-phase strategy. Recombinant and synthetic arenicins were purified, and their antimicrobial and spectroscopic properties were analyzed. NMR investigation shows that in water solution arenicin-2 displays a prolonged beta-hairpin, formed by two antiparallel beta-strands and stabilized by one disulfide and nine hydrogen bonds. A significant right-handed twist in the beta-sheet is deprived the peptide surface of amphipathicity. CD spectroscopic analysis indicates that arenicin-2 binds to the SDS and DPC micelles, and conformation of the peptide is significantly changed upon binding. Arenicin strongly binds to anionic lipid (POPE/POPG) vesicles in contrast with zwitterionic (POPC) ones. These results suggest that arenicins are membrane active peptides and point to possible mechanism of their selectivity toward bacterial cells.
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| 17587576 |
Gypsophin: a novel alpha-glucosidase inhibitory cyclic peptide from the roots of Gypsophila oldhamiana |
10.1016/j.bmcl.2007.06.011. |
Bioorg Med Chem Lett |
Gypsophin: a novel alpha-glucosidase inhibitory cyclic peptide from the roots of Gypsophila oldhamiana
Abstract
- An unusual new cyclic peptide with a pyrrolidine-2,5-dione unit, gypsophin (1), was isolated from Gypsophila oldhamiana. Its structure was elucidated by the spectroscopic evidences. The stereochemistry was determined by application of the Marfey's method and the single-crystal X-ray diffraction. Compound 1 exhibited inhibitory activity against alpha-glucosidase with IC50 of 305 microM.
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| 17587677 |
Novel cyclic peptide, epichlicin, from the endophytic fungus, Epichloe typhina |
10.1271/bbb.60700. |
Biosci Biotechnol Biochem |
Novel cyclic peptide, epichlicin, from the endophytic fungus, Epichloe typhina
Abstract
- The novel cyclic peptide, epichlicin, was isolated from Epichloe typhina, an endophytic fungus of the timothy plant (Phleum pretense L.). Its structure was determined by NMR studies and by mass spectrometry. Enantiomers of 3-amino tetradecanoic acid, a constituent amino acid of epichlicin, were synthesized as authentic standards. The stereochemistry of each amino acid was elucidated through a combination of the advanced Marfey method and chemical manipulation. Epichlicin showed inhibitory activity toward the spore germination of Cladosporium phlei, a pathogenic fungus of the timothy plant at an IC50 value of 22 nM.
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| 17590333 |
Convergent synthesis and in vivo inhibitory effect on fat accumulation of (-)-ternatin, a highly N-methylated cyclic peptide |
10.1016/j.bmcl.2007.06.015. |
Bioorg Med Chem Lett |
Convergent synthesis and in vivo inhibitory effect on fat accumulation of (-)-ternatin, a highly N-methylated cyclic peptide
Abstract
- (-)-Ternatin (1), a highly N-methylated cyclic heptapeptide, is a potent inhibitor of fat accumulation against 3T3-L1 murine adipocytes (EC50 = 0.14 microg/mL) [Shimokawa, K.; Mashima, I.; Asai, A.; Yamada, K.; Kita, M.; Uemura, D. Tetrahedron Lett. 2006, 47, 4445]. Compound 1 was synthesized from Boc-protected amino acids in solution. Upon treatment with 1 at 5 mg/kg/day, increases in body weight and fat accumulation in high-fat-fed mice were both significantly suppressed.
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| 17602586 |
Cyclic depsipeptides, ichthyopeptins A and B, from Microcystis ichthyoblabe |
10.1021/np060303s. |
J Nat Prod |
Cyclic depsipeptides, ichthyopeptins A and B, from Microcystis ichthyoblabe
Abstract
- Bioassay-guided isolation of antiviral compounds from the cultured cyanobacterium Microcystis ichthyoblabe provided two novel cyclic depsipeptides, ichthyopeptins A (1) and B (2). Their structures were determined by 1D (1H and 13C) and 2D (COSY, TOCSY, ROESY, HMQC, and HMBC) NMR spectra, ESIMS-MS, and amino acid analysis. The fraction containing both cyclic depsipeptides exhibited antiviral activity against influenza A virus with an IC50 value of 12.5 microg/mL.
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| 17603546 |
A functional comparison of recombinant and native somatostatin sst2 receptor variants in epithelia |
10.1038/sj.bjp.0707365. |
Br J Pharmacol |
A functional comparison of recombinant and native somatostatin sst2 receptor variants in epithelia
Abstract
- Somatostatin (SRIF-14) exerts broad spectrum antisecretory effects by activating the somatostatin 2 (sst(2)) receptor. The rat (r) sst(2) receptor exists in 'long' (sst(2a)) and 'short' (sst(2b)) forms that differ in their C termini, while a single human (h) sst(2a) exists. This study compares the characteristics of recombinant rsst(2a), rsst(2b) and hsst(2a) activation in human epithelia, and with native sst(2) responses in rat colon.
Epithelial layers of each clone or rat colon were placed in Ussing chambers and short-circuit current (I (SC)) measured in response to SRIF-14 and chosen analogues. The relative potencies and ability to cause desensitization to SRIF-14 were assessed, and the affinities of the sst(2) antagonist, D-Tyr(8) CYN154806 for hsst(2a), rsst(2a) and native rat colon sst(2) receptors were established.
Basolateral SRIF-14 responses were transient in hsst(2a) and rsst(2a) epithelia, but prolonged in rsst(2b)-expressing cells. Activation of rsst(2a) resulted in significant desensitization to SRIF-14 and receptor phosphorylation, whereas the rsst(2b) receptor did neither. Sst(2)-preferred agonists (BIM23190C and BIM23027) reduced I (sc) with similar potency and both caused complete desensitization to SRIF-14. CYN154806 antagonized hsst(2a) and rsst(2a) receptors with pK (B) values of 7.9 and 7.8, respectively. In rat colon mucosa, CYN154806 blocked SRIF-14 responses with a pA (2) value of 8.2, and BIM23190C responses with a pK (B) of 8.4.
SRIF-14 caused rapid rsst(2a) receptor phosphorylation and desensitization of epithelial antisecretory responses, neither of which occurred with the rsst(2b) receptor. These mechanisms are most likely to be a prerequisite for sensitivity to sst(2)-analogues with radiotherapeutic potential.
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| 17604256 |
Synthetic and pharmacological studies on longicalycinin A |
None |
Pak J Pharm Sci |
Synthetic and pharmacological studies on longicalycinin A
Abstract
- Present investigation describes the synthesis of a natural phenylalanine-rich cyclopolypeptide longicalycinin A (10) by coupling of dipeptide unit Boc-L-phe-L-tyr-OH with tripeptide unit L-pro-L-phe-gly-OMe followed by cyclization of linear segment. Synthesized cyclic pentapeptide was characterized by spectral techniques including FTIR, 1H/13C NMR, FAB MS and elemental analysis and screened for different pharmacological activities. It was found that it has good anthelmintic activity against Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus sp. at 2 mg/ml concentration, in addition to high cytotoxicity against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines with CTC50 values of 2.62 and 6.37 microM. Dermatophytes were found to be moderately sensitive towards newly synthesized peptide.
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| 17604723 |
HEF1-dependent Aurora A activation induces disassembly of the primary cilium. |
10.1016/j.cell.2007.04.035 |
Cell |
HEF1-dependent Aurora A activation induces disassembly of the primary cilium.
Abstract
- The mammalian cilium protrudes from the apical/lumenal surface of polarized cells and acts as a sensor of environmental cues. Numerous developmental disorders and pathological conditions have been shown to arise from defects in cilia-associated signaling proteins. Despite mounting evidence that cilia are essential sites for coordination of cell signaling, little is known about the cellular mechanisms controlling their formation and disassembly. Here, we show that interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly. We show that this pathway is both necessary and sufficient for ciliary resorption and that it constitutes an unexpected nonmitotic activity of AurA in vertebrates. Moreover, we demonstrate that small molecule inhibitors of AurA and HDAC6 selectively stabilize cilia from regulated resorption cues, suggesting a novel mode of action for these clinical agents.
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| 17605642 |
AGI-1067, a novel vascular protectant, anti-inflammatory drug and mild antiplatelet agent for treatment of atherosclerosis |
10.1586/14779072.5.4.635. |
Expert Rev Cardiovasc Ther |
AGI-1067, a novel vascular protectant, anti-inflammatory drug and mild antiplatelet agent for treatment of atherosclerosis
Abstract
- Oxidation-sensitive signals play an important role in platelet activation. AGI-1067 is a novel, phenolic, intra- and extracellular antioxidant that inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. AGI-1067 is the metabolically stable monosuccinic acid ester of probucol, and a potent phenolic antioxidant representing a novel class of orally bioavailable compounds termed vascular protectants. AGI-1067 exhibits antioxidant activity equipotent to probucol. In addition, animal studies have demonstrated dual pharmacological activities of AGI-1067: the ability to block the expression of oxidation-sensitive inflammatory genes including genes that code for vascular cell adhesion molecule-1 and monocyte chemotactic protein-1. Importantly, AGI-1067 also exhibits mild antiplatelet properties inhibiting surface expression of various key platelet receptors, the formation of platelet monocyte microparticles and PAR-1 thrombin receptors. AGI-1067 is currently being tested in the late trials, and if proven to improve clinical outcomes (ARISE trial), the drug will ultimately be used in patients with different manifestations of atherosclerosis and atherothrombosis.
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| 17607734 |
Uptake of microcystins-LR and -LF (cyanobacterial toxins) in seedlings of several important agricultural plant species and the correlation with cellular damage (lipid peroxidation) |
10.1002/tox.20266. |
Environ Toxicol |
Uptake of microcystins-LR and -LF (cyanobacterial toxins) in seedlings of several important agricultural plant species and the correlation with cellular damage (lipid peroxidation)
Abstract
- Plants used for agriculture may come into contact with cyanobacterial toxins via spray irrigation when surface water bodies containing cyanobacteria are used as the water source. As many of the bloom forming cyanobacteria are known to produce a variety of toxins, the possibility of uptake of toxins in these plants seems possible. With this study the uptake of two microcystins (MC-LR and MC-LF) as well as MC-LR within a cyanobacterial crude extract in several important agricultural plants is presented. Especially high uptake values in roots of alfalfa and wheat, using an ELISA kit for microcystin detection, is shown. In general, concentrations in the shoot occur at a much lower level than in the root. The amount of toxin is correlated with cellular damage in the seedlings using lipid peroxidation as an indicator. Good correlation was shown between toxin uptake and lipid peroxidation in the seedlings. The exposure of agriculturally important crop plants to cyanobacterial toxins via spray irrigation or watering is a potential concern for human health, as these toxins may accumulate in plant tissues and may therefore be carried through the food chain.
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