| 18008336 |
Cyclotides as natural anti-HIV agents |
10.1002/bip.20886. |
Biopolymers |
Cyclotides as natural anti-HIV agents
Abstract
- Cyclotides are disulfide rich macrocyclic plant peptides that are defined by their unique topology in which a head-to-tail cyclized backbone is knotted by the interlocking arrangement of three disulfide bonds. This cyclic cystine knot motif gives the cyclotides exceptional resistance to thermal, chemical, or enzymatic degradation. Over 100 cyclotides have been reported and display a variety of biological activities, including a cytoprotective effect against HIV infected cells. It has been hypothesized that cyclotides from one subfamily, the Möbius subfamily, may be more appropriate than bracelet cyclotides as drug candidates given their lower toxicity to uninfected cells. Here, we report the anti-HIV and cytotoxic effects of three cyclotides, including two from the Möbius subfamily. We show that Möbius cyclotides have comparable inhibitory activity against HIV infection to bracelet cyclotides and that they are generally less cytotoxic to the target cells. To explore the structure activity relationships (SARs) of the 29 cyclotides tested so far for anti-HIV activity, we modeled the structures of the 21 cyclotides whose structures have not been previously solved. We show that within cyclotide subfamilies there is a correlation between hydrophobicity of certain loop regions and HIV inhibition. We also show that charged residues in these loops impact on the activity of the cyclotides, presumably by modulating membrane binding. In addition to providing new SAR data, this report is a mini-review that collates all cyclotide anti-HIV information reported so far and provides a resource for future studies on the therapeutic potential of cyclotides as natural anti-HIV agents.
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| 18020563 |
Follitropin alpha in infertility: a review |
10.2165/00063030-199809030-00006. |
BioDrugs |
Follitropin alpha in infertility: a review
Abstract
- Follitropin alpha (recombinant human follicle-stimulating hormone; follitropin alfa) is a recombinant form of follicle-stimulating hormone (FSH), an endogenous gonadotrophin. Unlike FSH products derived from urine [menotropins (human menopausal gonadotrophins), urofollitropin and highly purified urofollitropin], follitropin alpha is readily available and shows batch-to-batch consistency. As well, it is free of luteinising hormone (LH) activity and contaminant urinary proteins and can be self-administered subcutaneously. In women undergoing in vitro fertilisation-embryo transfer (IVF-ET), follitropin alpha appears to have a greater stimulatory effect on follicular development than urine-derived FSH products as a group. In direct comparisons it had similar effects to urofollitropin but produced more oocytes per stimulated cycle than highly purified urofollitropin and menotropins. Preliminary results of 1 small trial indicate similar efficacy for follitropin alpha and follitropin beta. Rates of pregnancy, live births and multiple births have been similar among all treatment groups. As ovulation induction in women with clomifene-resistant WHO group II anovulation, follitropin alpha produces rates of ovulation, follicular development and pregnancy resembling those seen with urofollitropin or highly purified urofollitropin. A long term low-dose regimen of follitropin alpha is associated with a lower number of follicles and a trend toward fewer multiple births compared with conventional follitropin alpha or urofollitropin regimens. Data from women with WHO group I anovulation and from infertile men are scant. Tolerability has not differed between follitropin alpha and other FSH products. The incidence of general events (e.g. headache, nausea, ovarian cyst), local irritations at injection site and ovarian hyperstimulation syndrome resembled those for comparator FSH products. However, it appears that follitropin alpha can be tolerated in instances of severe allergic reaction to urine-derived products.
In women undergoing IVF-ET, follitropin alpha appears to have a greater stimulatory effect on follicle development than urine-derived FSH products as a group and is at least as well tolerated as these preparations; preliminary data indicate similar efficacy to follitropin beta. At present, its efficacy in women with WHO group II anovulation disorder has been shown to be similar to that of the older products. Compared with urinary FSH products, the benefits of follitropin alpha lie in its reliable supply, consistency of production, lack of contaminant urinary proteins and ease of self-administration. Given these practical advantages, and the apparently greater effect on follicular development overall in women undergoing IVF-ET, recombinant products such as follitropin alpha are expected to eventually replace older urine-derived FSH preparations and claim a prominent position in the treatment of infertility.
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| 18025465 |
Gene family encoding the major toxins of lethal Amanita mushrooms |
10.1073/pnas.0707340104. |
Proc Natl Acad Sci U S A |
Gene family encoding the major toxins of lethal Amanita mushrooms
Abstract
- Amatoxins, the lethal constituents of poisonous mushrooms in the genus Amanita, are bicyclic octapeptides. Two genes in A. bisporigera, AMA1 and PHA1, directly encode alpha-amanitin, an amatoxin, and the related bicyclic heptapeptide phallacidin, a phallotoxin, indicating that these compounds are synthesized on ribosomes and not by nonribosomal peptide synthetases. alpha-Amanitin and phallacidin are synthesized as proproteins of 35 and 34 amino acids, respectively, from which they are predicted to be cleaved by a prolyl oligopeptidase. AMA1 and PHA1 are present in other toxic species of Amanita section Phalloidae but are absent from nontoxic species in other sections. The genomes of A. bisporigera and A. phalloides contain multiple sequences related to AMA1 and PHA1. The predicted protein products of this family of genes are characterized by a hypervariable "toxin" region capable of encoding a wide variety of peptides of 7-10 amino acids flanked by conserved sequences. Our results suggest that these fungi have a broad capacity to synthesize cyclic peptides on ribosomes.
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| 18039827 |
Characterization of the structural gene encoding nisin F, a new lantibiotic produced by a Lactococcus lactis subsp. lactis isolate from freshwater catfish (Clarias gariepinus) |
10.1128/AEM.01862-07. |
Appl Environ Microbiol |
Characterization of the structural gene encoding nisin F, a new lantibiotic produced by a Lactococcus lactis subsp. lactis isolate from freshwater catfish (Clarias gariepinus)
Abstract
- Lactococcus lactis F10, isolated from freshwater catfish, produces a bacteriocin (BacF) active against Staphylococcus aureus, Staphylococcus carnosus, Lactobacillus curvatus, Lactobacillus plantarum, and Lactobacillus reuteri. The operon encoding BacF is located on a plasmid. Sequencing of the structural gene revealed no homology to other nisin genes. Nisin F is described.
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| 18045938 |
Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of Kaposi's sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor |
10.1128/JVI.01673-07. |
J Virol |
Integrin alphaVbeta3 Binds to the RGD motif of glycoprotein B of Kaposi's sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor
Abstract
- Kaposi's sarcoma-associated herpesvirus (KSHV) envelope-associated glycoprotein B (gB) is involved in the initial steps of binding to host cells during KSHV infection. gB contains an RGD motif reported to bind the integrin alpha(3)beta(1) during virus entry. Although the ligand specificity of alpha(3)beta(1) has been controversial, current literature indicates that alpha(3)beta(1) ligand recognition is independent of RGD. We compared alpha(3)beta(1) to the RGD-binding integrin, alpha(V)beta(3), for binding to envelope-associated gB and a gB(RGD) peptide. Adhesion assays demonstrated that beta(3)-CHO cells overexpressing alpha(V)beta(3) specifically bound gB(RGD), whereas alpha(3)-CHO cells overexpressing alpha(3)beta(1) did not. Function-blocking antibodies to alpha(V)beta(3) inhibited the adhesion of HT1080 fibrosarcoma cells to gB(RGD), while antibodies to alpha(3)beta(1) did not. Using affinity-purified integrins and confocal microscopy, alpha(V)beta(3) bound to gB(RGD) and KSHV virions, demonstrating direct receptor-ligand interactions. Specific alpha(V)beta(3) antagonists, including cyclic and dicyclic RGD peptides and alpha(V)beta(3) function-blocking antibodies, inhibited KSHV infection by 70 to 80%. Keratinocytes from alpha(3)-null mice lacking alpha(3)beta(1) were fully competent for infection by KSHV, and reconstitution of alpha(3)beta(1) function by transfection with alpha(3) cDNA reduced KSHV infectivity from 74% to 55%. Additional inhibitory effects of alpha(3)beta(1) on the cell surface expression of alpha(V)beta(3) and on alpha(V)beta(3)-mediated adhesion of alpha(3)-CHO cells overexpressing alpha(3)beta(1) were detected, consistent with previous reports of transdominant inhibition of alpha(V)beta(3) function by alpha(3)beta(1). These observations may explain previous reports of an inhibition of KSHV infection by soluble alpha(3)beta(1). Our studies demonstrate that alpha(V)beta(3) is a cellular receptor mediating both the cell adhesion and entry of KSHV into target cells through binding the virion-associated gB(RGD).
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| 18046415 |
Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface |
10.1038/nature05998. |
Nature |
Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface
Abstract
- Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one kinase domain induces an active conformation in the other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3-5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a approximately 25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition.
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| 18051337 |
Antifungal cyclopeptolide from fungal saprophytic antagonist Ulocladium atrum |
None |
J Microbiol Biotechnol |
Antifungal cyclopeptolide from fungal saprophytic antagonist Ulocladium atrum
Abstract
- The saprophytic fungus Ulocladium atrum Preuss is a promising biological control agent for Botrytis cinerea in greenhouse- and field-grown crops. However, despite its known potent antifungal activity, no antifungal substance has yet been reported. In an effort to characterize the antifungal substance from U atrum, we isolated an antibiotic peptide. Based on extensive spectroscopic analyses, its structure was established as a cyclopeptolide with a high portion of N-methylated amino acids, and its 1H and 13C chemical shifts were completely assigned based on extensive 1D and 2D NMR experiments. Compound 1 exhibited potent antifungal activity against the plant pathogenic fungus Botrytis cinerea and moderate activity against Alternaria alternate and Magnaporthe grisea.
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| 18056275 |
Telithromycin and quinupristin-dalfopristin induce delayed death in Plasmodium falciparum |
10.1128/AAC.00892-07. |
Antimicrob Agents Chemother |
Telithromycin and quinupristin-dalfopristin induce delayed death in Plasmodium falciparum
Abstract
- Antibacterial agents are used in malaria therapy due to their effect on two prokaryote organelles, the mitochondrion and the apicoplast. We demonstrate here that the ribosome-blocking antibiotics telithromycin and quinupristin-dalfopristin, but not linezolid, inhibit the growth of Plasmodium falciparum. Both drugs induce delayed death in the parasite, suggesting that their effect involves the impairment of apicoplast translation processes.
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| 18061663 |
Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans |
10.1016/j.npep.2007.09.006. |
Neuropeptides |
Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans
Abstract
- Cortistatin (CST), a neuropeptide with high structural homology with somatostatin (SST), binds all SST receptor (SST-R) subtypes but, unlike SST, also shows high binding affinity to ghrelin receptor (GHS-R1a). CST exerts the same endocrine activities of SST in humans, suggesting that the activation of the SST-R might mask the potential interaction with ghrelin system. CST-8, a synthetic CST-analogue devoid of any binding affinity to SST-R but capable to bind the GHS-R1a, has been reported able to exert antagonistic effects on ghrelin actions either in vitro or in vivo in animals. We studied the effects of CST-8 (2.0 microg/kg i.v. as a bolus or 2.0 microg/kg/h i.v. as infusion) on both spontaneous and ghrelin- or hexarelin- (1.0 microg/kg i.v. as bolus) stimulated GH, PRL, ACTH and cortisol secretion in 6 normal volunteers. During saline, no change occurred in GH and PRL levels while a spontaneous ACTH and cortisol decrease was observed. As expected, both ghrelin and hexarelin stimulated GH, PRL, ACTH and cortisol secretion (p<0.05). CST-8, administered either as bolus or as continuous infusion, did not modify both spontaneous and ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. In conclusion, CST-8 seems devoid of any modulatory action on either spontaneous or ghrelin-stimulated somatotroph, lactotroph and corticotroph secretion in humans in vivo. These negative results do not per se exclude that, even at these doses, CST-8 might have some neuroendocrine effects after prolonged treatment or that, at higher doses, may be able to effectively antagonize ghrelin action in humans. However, these data strongly suggest that CST-8 is not a promising candidate as GHS-R1a antagonist for human studies to explore the functional interaction between ghrelin and cortistatin systems.
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| 18065693 |
A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia |
10.1182/blood-2007-09-112615. |
Blood |
A nonsynonymous SNP in the ITGB3 gene disrupts the conserved membrane-proximal cytoplasmic salt bridge in the alphaIIbbeta3 integrin and cosegregates dominantly with abnormal proplatelet formation and macrothrombocytopenia
Abstract
- We report a 3-generation pedigree with 5 individuals affected with a dominantly inherited macrothrombocytopenia. All 5 carry 2 nonsynonymous mutations resulting in a D723H mutation in the beta3 integrin and a P53L mutation in glycoprotein (GP) Ibalpha. We show that GPIbalpha-L53 is phenotypically silent, being also present in 3 unaffected pedigree members and in 7 of 1639 healthy controls. The beta3-H723 causes constitutive, albeit partial, activation of the alphaIIbbeta3 complex by disruption of the highly conserved cytoplasmic salt bridge with arginine 995 in the alphaIIb integrin as evidenced by increased PAC-1 but not fibrinogen binding to the patients' resting platelets. This was confirmed in CHO alphaIIbbeta3-H723 transfectants, which also exhibited increased PAC-1 binding, increased adhesion to von Willebrand factor (VWF) in static conditions and to fibrinogen under shear stress. Crucially, we show that in the presence of fibrinogen, alphaIIbbeta3-H723, but not wild-type alphaIIbbeta3, generates a signal that leads to the formation of proplatelet-like protrusions in transfected CHO cells. Abnormal proplatelet formation was confirmed in the propositus's CD34+ stem cell-derived megakaryocytes. We conclude that the constitutive activation of the alphaIIbbeta3-H723 receptor causes abnormal proplatelet formation, leading to incorrect sizing of platelets and the thrombocytopenia observed in the pedigree.
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| 18072745 |
New cyclic peptides from the seeds of Annona squamosa L. and their anti-inflammatory activities |
10.1021/jf072594w. |
J Agric Food Chem |
New cyclic peptides from the seeds of Annona squamosa L. and their anti-inflammatory activities
Abstract
- Two new cyclic peptides, cyclosquamosin H ( 1) and I ( 2), together with six known cyclic peptides, squamin A ( 3), squamin B ( 4), cyclosquamosin A ( 6), cyclosquamosin D ( 7), cyclosquamosin E ( 8), and cherimolacyclopeptide B ( 9), were isolated from the seeds of Annona squamosa. All structures were confirmed by 2D nuclear magnetic resonance, chemical evidence, and electrospray ionization-mass spectromotry/mass spectrometry (ESI-MS/MS). Compound 9 was isolated from this plant for the first time. In the anti-inflammatory assay, compound 7 showed an inhibitory effect on the production of pro-inflammatory cytokines within lipopolysaccharide and Pam3Cys-stimulated J774A.1 macrophages.
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| 18075648 |
Synthesis and inhibitory effect on fat accumulation of (-)-ternatin derivatives modified in the beta-OH-D-Leu(7) moiety |
10.1039/b714710d. |
Org Biomol Chem |
Synthesis and inhibitory effect on fat accumulation of (-)-ternatin derivatives modified in the beta-OH-D-Leu(7) moiety
Abstract
- An efficient synthesis of (-)-ternatin derivatives directed toward their SAR at the beta-OH-D-Leu(7) moiety and their biological activities against 3T3-L1 murine adipocytes are described.
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| 18081258 |
Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis |
10.1021/np070393g. |
J Nat Prod |
Anti-HIV cyclotides from the Chinese medicinal herb Viola yedoensis
Abstract
- Cyclotides are macrocyclic plant peptides characterized by a knotted arrangement of three disulfide bonds. They display a range of interesting bioactivities, including anti-HIV and insecticidal activities. More than 100 different cyclotides have been isolated from two phylogenetically distant plant families, the Rubiaceae and Violaceae. In this study we have characterized the cyclotides from Viola yedoensis, an important Chinese herb from the Violaceae family that has been reported to contain potential anti-HIV agents. From V. yedoensis five new and three known cyclotides were identified and shown to have anti-HIV activity. The most active of these is cycloviolacin Y5, which is one of the most potent of all cyclotides tested so far using in vitro XTT-based anti-HIV assays. Cycloviolacin Y5 is the most hydrophobic of the cyclotides from V. yedoensis. We show that there is a positive correlation between the hydrophobicity and the anti-HIV activity of the new cyclotides and that this trend tracks with their ability to disrupt membranes, as judged from hemolytic assays on human erythrocytes.
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| 18087804 |
Synthetic and biological studies on natural cyclic heptapeptide: segetalin E |
10.1007/BF02977360. |
Arch Pharm Res |
Synthetic and biological studies on natural cyclic heptapeptide: segetalin E
Abstract
- Present investigation describes the first total synthesis of a proline-rich cyclic peptide segetalin E (8) by solution phase technique. The chemical structure of the compound was elucidated by FT-IR, 1H-NMR, 13C-NMR, FAB-MS spectral data and elemental analyses. The newly synthesized peptide was subjected to pharmacological screening and found to exhibit high cytotoxicity against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines with IC50 values of 3.71 and 9.11 microM, in addition to good anthelmintic activity against earthworms M. konkanensis and P. corethruses at a dose of 2 mg/mL.
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| 18088087 |
Phosphoproteome of resting human platelets |
10.1021/pr0704130. |
J Proteome Res |
Phosphoproteome of resting human platelets
Abstract
- Beside their main physiological function in hemostasis, platelets are also highly involved in pathological processes, such as atherothrombosis and inflammation. During hemostasis, binding of adhesive substrates to tyrosine-kinase-linked adhesion receptors and/or soluble agonists to G-protein coupled receptors leads to a cascade of intracellular signaling processes based on substrate (de)phosphorylation. The same mechanisms are involved in platelet activation at sites of atherosclerotic plaque rupture, contributing to vessel occlusion and consequently to pathologic states, such as myocardial infarction, stroke, or peripheral artery disease. To gain a deeper insight into platelet function, we analyzed the phosphoproteome of resting platelets and identified 564 phosphorylation sites from more than 270 proteins, of which many have not been described in platelets before. Among those were several unknown potential protein kinase A (PKA) and protein kinase G (PKG) substrates. Because platelet inhibition is tightly regulated especially by PKA and PKG activity, these proteins may represent important new targets for cardiovascular research. Thus, our finding that GPIbalpha is phosphorylated at Ser603 in resting platelets may represent a novel mechanism for the regulation of one of the most important platelet receptor (GPIb-IX-V) mediated signaling pathways by PKA/PKG.
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