| 29499484 |
β,γ-diamino acids as building blocks for new analogues of Gramicidin S: Synthesis and biological activity |
10.1016/j.ejmech.2018.02.053. |
Eur J Med Chem |
β,γ-diamino acids as building blocks for new analogues of Gramicidin S: Synthesis and biological activity
Abstract
- We describe here the synthesis and biological activity study of a pair of diastereomeric analogues of Gramicidin S using β,γ-diamino acids as β-turn mimic. The synthesis of the orthogonally protected β,γ-diamino acids was achieved in 6 steps starting from d-alanine. The analogues were then synthesized in solution phase and on solid phase. Biological activity tests showed that, compared with Gramicidin S, both analogues exerted diminished hemolytic activity while they retained interesting antibacterial activity.
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| 29512653 |
Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis |
10.1038/nature26153. |
Nature |
Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis
Abstract
- The insulin receptor is a dimeric protein that has a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels. Insulin receptor dysfunction has been associated with many diseases, including diabetes, cancer and Alzheimer's disease. The primary sequence of the receptor has been known since the 1980s, and is composed of an extracellular portion (the ectodomain, ECD), a single transmembrane helix and an intracellular tyrosine kinase domain. Binding of insulin to the dimeric ECD triggers auto-phosphorylation of the tyrosine kinase domain and subsequent activation of downstream signalling molecules. Biochemical and mutagenesis data have identified two putative insulin-binding sites, S1 and S2. The structures of insulin bound to an ECD fragment containing S1 and of the apo ectodomain have previously been reported, but details of insulin binding to the full receptor and the signal propagation mechanism are still not understood. Here we report single-particle cryo-electron microscopy reconstructions of the 1:2 (4.3 Å) and 1:1 (7.4 Å) complexes of the insulin receptor ECD dimer with insulin. The symmetrical 4.3 Å structure shows two insulin molecules per dimer, each bound between the leucine-rich subdomain L1 of one monomer and the first fibronectin-like domain (FnIII-1) of the other monomer, and making extensive interactions with the α-subunit C-terminal helix (α-CT helix). The 7.4 Å structure has only one similarly bound insulin per receptor dimer. The structures confirm the binding interactions at S1 and define the full S2 binding site. These insulin receptor states suggest that recruitment of the α-CT helix upon binding of the first insulin changes the relative subdomain orientations and triggers downstream signal propagation.
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| 29561811 |
Heterophyllin B Ameliorates Lipopolysaccharide-Induced Inflammation and Oxidative Stress in RAW 264.7 Macrophages by Suppressing the PI3K/Akt Pathways |
10.3390/molecules23040717. |
Molecules |
Heterophyllin B Ameliorates Lipopolysaccharide-Induced Inflammation and Oxidative Stress in RAW 264.7 Macrophages by Suppressing the PI3K/Akt Pathways
Abstract
- Heterophyllin B (HB), an active cyclic peptide, is a compound existing in the ethyl acetate extract of (Miq.) Pax and exhibited the activity of inhibiting the production of NO and cytokines, such as IL-1β and IL-6, in LPS-stimulated RAW 264.7 macrophages. In addition, HB suppressed the production of ROS and the apoptosis induced by LPS in RAW 264.7 macrophages. The underlying mechanism was investigated in the LPS-induced RAW 264.7 cells. The results showed that HB decreased the level of IL-1β and IL-6 expression by qRT-PCR analysis. HB up-regulated the relative ratio of p-AKT/AKT and p-PI3K/PI3K as indicated by western blot analysis. In summary, HB inhibited the LPS-induced inflammation and apoptosis through the PI3K/Akt signaling pathways and represented a potential therapeutic target for treatment of inflammatory diseases.
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| 29592954 |
Synergistic activity of cosecreted natural products from amoebae-associated bacteria |
10.1073/pnas.1721790115. |
Proc Natl Acad Sci U S A |
Synergistic activity of cosecreted natural products from amoebae-associated bacteria
Abstract
- Investigating microbial interactions from an ecological perspective is a particularly fruitful approach to unveil both new chemistry and bioactivity. Microbial predator-prey interactions in particular rely on natural products as signal or defense molecules. In this context, we identified a grazing-resistant strain, isolated from the bacterivorous amoeba Genome analysis of this bacterium revealed the presence of two biosynthetic gene clusters that were found adjacent to each other on a contiguous stretch of the bacterial genome. Although one cluster codes for the polyketide synthase producing the known antibiotic mupirocin, the other cluster encodes a nonribosomal peptide synthetase leading to the unreported cyclic lipopeptide jessenipeptin. We describe its complete structure elucidation, as well as its synergistic activity against methicillin-resistant , when in combination with mupirocin. Both biosynthetic gene clusters are regulated by quorum-sensing systems, with 3-oxo-decanoyl homoserine lactone (3-oxo-C10-AHL) and hexanoyl homoserine lactone (C6-AHL) being the respective signal molecules. This study highlights the regulation, richness, and complex interplay of bacterial natural products that emerge in the context of microbial competition.
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| 29606488 |
Discovery of new A- and B-type laxaphycins with synergistic anticancer activity |
10.1016/j.bmc.2018.03.022. |
Bioorg Med Chem |
Discovery of new A- and B-type laxaphycins with synergistic anticancer activity
Abstract
- Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey's analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC of 1.7 µM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells.
|
| 29610196 |
Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species |
10.1128/AAC.00111-18. |
Antimicrob Agents Chemother |
Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species
Abstract
- Systemic candidiasis is a growing health care concern that is becoming even more challenging due to the growing frequency of infections caused by multidrug-resistant (MDR) species. Thus, there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of θ-defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug-sensitive and drug-resistant clinical isolates of and non- species. Rhesus θ-defensin 1 (RTD-1), the prototype θ-defensin, was rapidly and potently fungicidal against drug-sensitive and MDR strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that by histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed much more rapidly and at a >200-fold lower concentration than that of Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to proteases for 2 h under conditions that rapidly and completely degraded Hst 5. MICs and minimum fungicidal concentrations (MFCs) of 14 natural θ-defensins isoforms against drug-resistant isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole-resistant organisms, including MDR These results point to the potential of macrocyclic θ-defensins as structural templates for the design of antifungal therapeutics.
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| 29623717 |
[Idiopathic thrombocytopenia refractery to therapy of cyclosporine A in clinical practice - case report] |
None |
Ceska Slov Farm |
[Idiopathic thrombocytopenia refractery to therapy of cyclosporine A in clinical practice - case report]
Abstract
- Primary immune thrombocytopenia (idiopathic thrombocytopenic purpura; ITP) is an autoimmune disorder characterized by isolated thrombocytopenia without abnormalities in the erythroid and myeloid/lymphoid lineages. The incidence of ITP in adults is estimated at approximately 1.6-3.9 per 100 000 persons/year. The aim of this study was to analyze a case report of a patient with diagnosed immune thrombocytopenia (D69.3) resistant to cyclosporine A therapy as well as an evaluation of factors that could contribute to an inadequate response to cyclosporine A. The results show a multifactorial origin of thrombocytopenia and a possible effect on refractivity to cyclosporine A therapy caused by long-term smoking, MDR-1 gene polymorphism, genetic predisposition to autoimmune diseases, allergic reactions as a manifestation of hypersensitivity in the immune system, controversial compliance of the patient, overcome infections as well as impact of drugs taken.Key words: immune thrombocytopenia refractery form cyclosporine A therapy platelets.
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| 29671350 |
Total synthesis and cyclization strategy of samoamide A, a cytotoxic cyclic octapeptide rich in proline and phenlalanine isolated from marine cyanobacterium |
10.1080/10286020.2018.1450391. |
J Asian Nat Prod Res |
Total synthesis and cyclization strategy of samoamide A, a cytotoxic cyclic octapeptide rich in proline and phenlalanine isolated from marine cyanobacterium
Abstract
- Samoamide A is a cyclic octapeptide rich in proline and phenylalanine residues isolated from an American Samoa marine cyanobacterium, which exhibits potent activity against H460 human non-small-cell lung cancer cells (IC of 1.1 μM). The first total synthesis of samoamide A was achieved by employing a strategy of a solid-phase peptide synthesis (SPPS) and a head-to-tail cyclization selecting free steric-hinrance connection sites. Then the final product was purified and identified. This strategy not only provides a basis in producing potent cytotoxic agents for drug discovery, but also provides a reference to the total synthesis of proline-rich peptides.
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| 29671790 |
Chemical Synthesis and Functional Analysis of VarvA Cyclotide |
10.3390/molecules23040952. |
Molecules |
Chemical Synthesis and Functional Analysis of VarvA Cyclotide
Abstract
- Cyclotides are circular peptides found in various plant families. A cyclized backbone, together with multiple disulfide bonds, confers the peptides’ exceptional stability against protease digestion and thermal denaturation. In addition, the features of these antimicrobial molecules make them suitable for use in animal farming, such as aquaculture. Fmoc solid phase peptide synthesis on 2-chlorotrityl chlorine (CTC) resin using the “tea-bag” approach was conducted to generate the VarvA cyclotide identified previously from . MALDI-TOF mass spectrometry determined the correct peptide amino acid sequence and the cyclization sites-critical in this multicyclic compound. The cyclotide showed antimicrobial activity against various Gram-negative bacteria, including recurrent pathogens present in Chilean aquaculture. The highest antimicrobial activity was found to be against . In addition, membrane blebbing on the bacterial surface after exposure to the cyclotide was visualized by SEM microscopy and the Sytox Green permeabilization assay showed the ability to disrupt the bacterial membrane. We postulate that this compound can be proposed for the control of fish farming infections.
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| 29686157 |
Antimicrobial Activity of Murepavadin Tested against Clinical Isolates of Pseudomonas aeruginosa from the United States, Europe, and China |
10.1128/AAC.00311-18. |
Antimicrob Agents Chemother |
Antimicrobial Activity of Murepavadin Tested against Clinical Isolates of Pseudomonas aeruginosa from the United States, Europe, and China
Abstract
- Murepavadin (formerly POL7080), a 14-amino-acid cyclic peptide, and comparators were tested by the broth microdilution method against 1,219 isolates from 112 medical centers. Murepavadin (MIC, 0.12/0.12 mg/liter) was 4- to 8-fold more active than colistin (MIC, 1/1 mg/liter) and polymyxin B (MIC, 0.5/1 mg/liter) and inhibited 99.1% of isolates at ≤0.5 mg/liter. Only 4 isolates (0.3%) exhibited murepavadin MICs of >2 mg/liter. Murepavadin was equally active against isolates from Europe, the United States, and China.
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| 29686660 |
Heterologous Production of a Novel Cyclic Peptide Compound, KK-1, in |
10.3389/fmicb.2018.00690. |
Front Microbiol |
Heterologous Production of a Novel Cyclic Peptide Compound, KK-1, in
Abstract
- A novel cyclic peptide compound, KK-1, was originally isolated from the plant-pathogenic fungus . It consists of 10 amino acid residues, including five -methylated amino acid residues, and has potent antifungal activity. Recently, the genome-sequencing analysis of was completed, and the biosynthetic genes involved in KK-1 production were predicted by using a novel gene cluster mining tool, MIDDAS-M. These genes form an approximately 75-kb cluster, which includes nine open reading frames, containing a non-ribosomal peptide synthetase (NRPS) gene. To determine whether the predicted genes were responsible for the biosynthesis of KK-1, we performed heterologous production of KK-1 in by introduction of the cluster genes into the genome of . The NRPS gene was split in two fragments and then reconstructed in the genome, because the gene was quite large (approximately 40 kb). The remaining seven genes in the cluster, excluding the regulatory gene , were simultaneously introduced into the strain of in which NRPS had already been incorporated. To evaluate the heterologous production of KK-1 in , gene expression was analyzed by RT-PCR and KK-1 productivity was quantified by HPLC. KK-1 was produced in variable quantities by a number of transformed strains, along with expression of the cluster genes. The amount of KK-1 produced by the strain with the greatest expression of all genes was lower than that produced by the original producer, . Therefore, expression of the cluster genes is necessary and sufficient for the heterologous production of KK-1 in , although there may be unknown factors limiting productivity in this species.
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| 29706375 |
Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial |
10.1016/S1470-2045(18)30147-5. |
Lancet Oncol |
Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial
Abstract
- The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer.
This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number , and is closed to accrual.
Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m on days 2 and 9, and balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia.
The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials.
Polyphor.
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| 29729580 |
Analysis of cyanobacterial metabolites in surface and raw drinking waters reveals more than microcystin |
10.1016/j.watres.2018.04.032. |
Water Res |
Analysis of cyanobacterial metabolites in surface and raw drinking waters reveals more than microcystin
Abstract
- Freshwater cyanobacterial blooms are becoming increasingly problematic in regions that rely on surface waters for drinking water production. Microcystins (MCs) are toxic peptides produced by multiple cyanobacterial genera with a global occurrence. Cyanobacteria also produce a variety of other toxic and/or otherwise bioactive peptides (TBPs) that have gained less attention including cyanopeptolins (Cpts), anabaenopeptins (Apts), and microginins (Mgn). In this study, we compared temporal and spatial trends of four MCs (MCLR, MCRR, MCYR, MCLA), three Cpts (Cpt1020, Cpt1041, Cpt1007), two Apts (AptF, AptB), and Mgn690 in raw drinking water and at six surface water locations above these drinking water intakes in a eutrophic lake. All four MC congeners and five of six TBPs were detected in lake and raw drinking water. Across all samples, MCLR was the most frequently detected metabolite (100% of samples) followed by MCRR (97%) > Cpt1007 (74%) > MCYR (69%) > AptF (67%) > MCLA (61%) > AptB (54%) > Mgn690 (29%) and Cpt1041 (15%). Mean concentrations of MCs, Apts, and Cpts into two drinking water intakes were 3.9 ± 4.7, 0.14 ± 0.21, and 0.38 ± 0.92, respectively. Mean concentrations in surface water were significantly higher (p < 0.05) than in drinking water intakes for MCs but not for Cpts and Apts. Temporal trends in MCs, Cpts, and Apts in the two raw drinking water intakes were significantly correlated (p < 0.05) with measures of cell abundance (chlorophyll-a, Microcystis cell density), UV absorbance, and turbidity in surface water. This study expands current information about cyanobacterial TBPs that occur in lakes and that enter drinking water treatment plants and underscores the need to determine the fate of less studied cyanobacterial metabolites during drinking water treatment that may exacerbate toxicity of more well-known cyanobacterial toxins.
|
| 29733353 |
Application of an agr-Specific Antivirulence Compound as Therapy for Staphylococcus aureus-Induced Inflammatory Skin Disease |
10.1093/infdis/jiy259. |
J Infect Dis |
Application of an agr-Specific Antivirulence Compound as Therapy for Staphylococcus aureus-Induced Inflammatory Skin Disease
Abstract
- Atopic dermatitis (AD) is a chronic inflammatory skin disease where more than 90% of patients affected are colonized with Staphylococcus aureus. In AD, S. aureus δ-toxin is a major virulence factor causing cutaneous inflammation via mast cell degranulation. δ-toxin is controlled by the S. aureus agr quorum sensing system, and thus we addressed whether interference with agr signaling would limit skin inflammation. Indeed, treatment of S. aureus with the agr-inhibitor solonamide B (SolB) abolished δ-toxin production and reduced skin inflammation in a mouse model of inflammatory skin disease, demonstrating the potential of antivirulence therapy in treating S. aureus-induced skin disorders.
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| 29738955 |
Lactam hybrid analogues of solonamide B and autoinducing peptides as potent S. aureus AgrC antagonists |
10.1016/j.ejmech.2018.04.053. |
Eur J Med Chem |
Lactam hybrid analogues of solonamide B and autoinducing peptides as potent S. aureus AgrC antagonists
Abstract
- Emergence of antibiotic-resistant bacteria constitutes an increasing threat to human health. For example, treatment options for Staphylococcus aureus infections is declining with the worldwide spreading of highly virulent community-associated methicillin-resistant S. aureus (CA-MRSA) strains. Anti-virulence therapy has been proposed as an alternative treatment strategy, as it typically involves inhibition of expression of virulence factors rather than direct bacterial killing, thereby attenuating the risk of resistance development. An intriguing target is the agr quorum-sensing system, which is a major inducer of virulence in CA-MRSA upon activation by agr-encoded staphylococcal autoinducing peptides (AIPs). In the present work a previously identified lactam hybrid analogue based on the marine depsipeptide solonamide B and the general structure of AIPs was investigated with respect to structure-function relationships. An array of 27 analogues exploring expansion of ring size, type of side chain, amino acid substitutions, and stereochemistry was designed and tested for AgrC-inhibitory activity. Interestingly, it was found that an analogue derived from the mirror image of the original hit proved to be the hitherto most efficient AgrC inhibitor resembling solonamide B in amino acid sequence. This and closely related compounds were 20- to 40-fold more potent in AgrC inhibition than the starting hit compound.
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