| 25384234 |
Triazene as a powerful tool for solid-phase derivatization of phenylalanine containing peptides: zygosporamide analogues as a proof of concept |
10.1021/jo501830w. |
J Org Chem |
Triazene as a powerful tool for solid-phase derivatization of phenylalanine containing peptides: zygosporamide analogues as a proof of concept
Abstract
- A novel method for the synthesis of para-substituted phenylalanine containing cyclic peptides is described. The main features of this strategy are the coupling of phenylalanine to the solid support through its side chain via a triazene linkage, on-resin cyclization of the peptide chain, cleavage of the cyclic peptide from the resin under mild acidic conditions and further transformation of the resulting diazonium salt. The usefulness of this approach is exemplified by the solid-phase synthesis of some derivatives of the naturally occurring cyclic depsipeptide zygosporamide.
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| 25419631 |
Cyclic depsipeptides as potential cancer therapeutics |
10.1097/CAD.0000000000000183. |
Anticancer Drugs |
Cyclic depsipeptides as potential cancer therapeutics
Abstract
- Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics.
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| 25451334 |
Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice |
10.1016/j.peptides.2014.10.013. |
Peptides |
Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice
Abstract
- Somatostatin interacts with five G-protein-coupled receptor (sst1-5). Octreotide, a stable sst2≫3≥5 agonist, exerts a visceral anti-hyperalgesic effect in experimental and clinical studies. Little is known on the receptor subtypes involved. We investigated the influence of the stable sst1-5 agonist, ODT8-SST and selective receptor subtype peptide agonists (3 or 10μg/mouse) injected intraperitoneally (ip) on visceral hypersensitivity in mice induced by repeated noxious colorectal distensions (four sets of three CRD, each at 55mmHg) or corticotropin-releasing factor receptor 1 agonist, cortagine given between two sets of graded CRD (15, 30, 45, and 60mmHg, three times each pressure). The mean visceromotor response (VMR) was assessed using a non-invasive manometry method and values were expressed as percentage of the VMR to the 1st set of CRD baseline or to the 60mmHg CRD, respectively. ODT8-SST (10μg) and the sst2 agonist, S-346-011 (3 and 10μg) prevented mechanically induced visceral hypersensitivity in the three sets of CRD, the sst1 agonist (10μg) blocked only the 2nd set and showed a trend at 3μg while the sst4 agonist had no effect. The selective sst2 antagonist, S-406-028 blocked the sst2 agonist but not the sst1 agonist effect. The sst1 agonist (3 and 10μg) prevented cortagine-induced hypersensitivity to CRD at each pressure while the sst2 agonist at 10μg reduced it. These data indicate that in addition to sst2, the sst1 agonist may provide a novel promising target to alleviate visceral hypersensitivity induced by mechanoreceptor sensitization and more prominently, stress-related visceral nociceptive sensitization.
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| 25485686 |
Lysocin E is a new antibiotic that targets menaqui in the bacterial membrane |
10.1038/nchembio.1710. |
Nat Chem Biol |
Lysocin E is a new antibiotic that targets menaqui in the bacterial membrane
Abstract
- To obtain therapeutically effective new antibiotics, we first searched for bacterial culture supernatants with antimicrobial activity in vitro and then performed a secondary screening using the silkworm infection model. Through further purification of the in vivo activity, we obtained a compound with a previously uncharacterized structure and named it 'lysocin E'. Lysocin E interacted with menaqui in the bacterial membrane to achieve its potent bactericidal activity, a mode of action distinct from that of any other known antibiotic, indicating that lysocin E comprises a new class of antibiotic. This is to our knowledge the first report of a direct interaction between a small chemical compound and menaqui that leads to bacterial killing. Furthermore, lysocin E decreased the mortality of infected mice. To our knowledge, lysocin E is the first compound identified and purified by quantitative measurement of therapeutic effects in an invertebrate infection model that exhibits robust in vivo effects in mammals.
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| 25488840 |
Synthesis and biological evaluation of the [d-MeAla(11)]-epimer of coibamide A |
10.1016/j.bmcl.2014.11.044. |
Bioorg Med Chem Lett |
Synthesis and biological evaluation of the [d-MeAla(11)]-epimer of coibamide A
Abstract
- Coibamide A is a highly potent antiproliferative cyclic depsipeptide, which was originally isolated from a Panamanian marine cyanobacterium. In this study, the synthesis of coibamide A has been investigated using Fmoc-based solid-phase peptide synthesis followed by the cleavage of the resulting linear peptide from the resin and its subsequent macrolactonization. The peptide sequence of the linear coibamide A precursor was constructed on a solid-support following the optimization of the coupling conditions, where numerous coupling agents were evaluated. The macrocyclization of the resulting linear peptide provided the [d-MeAla(11)]-epimer of coibamide A, which exhibited nanomolar cytotoxic activity towards a number of human cancer cell lines.
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| 25501912 |
Total synthesis of largamide B |
10.1039/c4cc08901d. |
Chem Commun (Camb) |
Total synthesis of largamide B
Abstract
- Total synthesis of the cyanobacterial metabolite largamide B and the disproval of its originally assigned stereochemistry as well as confirmation of the revised stereochemistry are reported.
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| 25504563 |
Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues |
10.1002/anie.201410270. |
Angew Chem Int Ed Engl |
Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues
Abstract
- Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action.
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| 25504752 |
Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models |
10.1158/1535-7163.MCT-14-0850. |
Mol Cancer Ther |
Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models
Abstract
- Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho-Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose-dependent inhibition of tumor growth in human xenograft models developed with non-Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer.
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| 25513892 |
Effects of hydrogen peroxide and ultrasound on biomass reduction and toxin release in the cyanobacterium, Microcystis aeruginosa |
10.3390/toxins6123260. |
Toxins (Basel) |
Effects of hydrogen peroxide and ultrasound on biomass reduction and toxin release in the cyanobacterium, Microcystis aeruginosa
Abstract
- Cyanobacterial blooms are expected to increase, and the toxins they produce threaten human health and impair ecosystem services. The reduction of the nutrient load of surface waters is the preferred way to prevent these blooms; however, this is not always feasible. Quick curative measures are therefore preferred in some cases. Two of these proposed measures, peroxide and ultrasound, were tested for their efficiency in reducing cyanobacterial biomass and potential release of cyanotoxins. Hereto, laboratory assays with a microcystin (MC)-producing cyanobacterium (Microcystis aeruginosa) were conducted. Peroxide effectively reduced M. aeruginosa biomass when dosed at 4 or 8 mg L-1, but not at 1 and 2 mg L-1. Peroxide dosed at 4 or 8 mg L-1 lowered total MC concentrations by 23%, yet led to a significant release of MCs into the water. Dissolved MC concentrations were nine-times (4 mg L-1) and 12-times (8 mg L-1 H2O2) higher than in the control. Cell lysis moreover increased the proportion of the dissolved hydrophobic variants, MC-LW and MC-LF (where L = Leucine, W = tryptophan, F = phenylalanine). Ultrasound treatment with commercial transducers sold for clearing ponds and lakes only caused minimal growth inhibition and some release of MCs into the water. Commercial ultrasound transducers are therefore ineffective at controlling cyanobacteria.
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| 25527531 |
Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate |
10.1128/AEM.03256-14. |
Appl Environ Microbiol |
Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate
Abstract
- Pneumocandins produced by the fungus Glarea lozoyensis are acylated cyclic hexapeptides of the echinocandin family. Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate. In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization. The pneumocandin biosynthetic gene cluster was previously elucidated by a whole-genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to produce exclusively pneumocandin B0. Disruption of GLOXY4, encoding a nonheme, α-ketoglutarate-dependent oxygenase, confirmed its involvement in l-leucine cyclization to form 4S-methyl-l-proline. The absence of 4S-methyl-l-proline abolishes pneumocandin A0 production, and 3S-hydroxyl-l-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0. Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4. This one-step genetic manipulation can rationally engineer a high-yield production strain.
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| 25557882 |
Generation of a genetically encoded, photoactivatable intein for the controlled production of cyclic peptides |
10.1002/anie.201409848. |
Angew Chem Int Ed Engl |
Generation of a genetically encoded, photoactivatable intein for the controlled production of cyclic peptides
Abstract
- Cyclic peptides are important natural products and hold great promise for the identification of new bioactive molecules. The split-intein-mediated SICLOPPS technology provides a generic access to fully genetically encoded head-to-tail cyclized peptides and large libraries thereof (SICLOPPS=split-intein circular ligation of peptides and proteins). However, owing to the spontaneous protein splicing reaction, product formation occurs inside cells, making peptide isolation inconvenient and precluding traditional in vitro assays for inhibitor discovery. The design of a genetically encoded, light-dependent intein using the photocaged tyrosine derivative ortho-nitrobenzyltyrosine incorporated at an internal, non-catalytic position is now reported. Stable intein precursors were purified from the E.coli expression host and subsequently subjected to light activation in vitro for both the regular protein splicing format and cyclic peptide production, including the natural product segetalin H as an example. The activity of the intein could also be triggered in living cells.
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| 25560210 |
The involvement of V1b-subtype vasopressin receptors in regulation of potassium ions excretion in the rat kidneys |
10.1134/S001249661406009X. |
Dokl Biol Sci |
The involvement of V1b-subtype vasopressin receptors in regulation of potassium ions excretion in the rat kidneys
Abstract
|
| 25562664 |
Depsipeptide companeramides from a Panamanian marine cyanobacterium associated with the coibamide producer |
10.1021/np5007907. |
J Nat Prod |
Depsipeptide companeramides from a Panamanian marine cyanobacterium associated with the coibamide producer
Abstract
- Two new cyclic depsipeptides, companeramides A (1) and B (2), have been isolated from the phylogenetically characterized cyanobacterial collection that yielded the previously reported cancer cell toxin coibamide A (collected from Coiba Island, Panama). The planar structures of the companeramides, which contain 3-amino-2-methyl-7-octynoic acid (Amoya), hydroxy isovaleric acid (Hiva), and eight α-amino acid units, were established by NMR spectroscopy and mass spectrometry. The absolute configuration of each companeramide was assigned using a combination of Marfey's methodology and chiral-phase HPLC analysis of complete and partial hydrolysis products compared to commercial and synthesized standards. Companeramides A (1) and B (2) showed high nanomolar in vitro antiplasmodial activity but were not overtly cytotoxic to four human cancer cell lines at the doses tested.
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| 25581598 |
Functional characterization of two naturally occurring mutations (Val514Ala and Ala575Val) in follicle-stimulating hormone receptor |
10.1210/jc.2014-3662. |
J Clin Endocrinol Metab |
Functional characterization of two naturally occurring mutations (Val514Ala and Ala575Val) in follicle-stimulating hormone receptor
Abstract
- Context:
Inactivating mutations have been reported in subjects with primary/secondary amenorrhea, whereas activating mutations are rare and seen only in women with ovarian hyperstimulation syndrome (OHSS). In the present study, we describe the functional characterization of the two mutations Val(514)Ala (novel mutation) and Ala(575)Val in FSH receptor (FSHR) identified in women with OHSS developed during in vitro fertilization and primary amenorrhea, respectively.
Objective:
The objective of the investigation was to study the effect of mutations (514 and 575) on FSHR activity by in vitro functional studies.
Setting:
The study was conducted at an academic research institute and a private in vitro fertilization clinic.
Methods:
The site-directed mutagenesis was carried out to generate the mutations at position 514 and 575 in pSG5-FSHR construct. Stable cell lines expressing wild type or each of the mutant receptor were generated using Chinese hamster ovary cells. Functional characteristics of both the mutant receptors were assessed by a radioreceptor assay and a cAMP assay.
Results:
The mutant receptor 514 showed increased cell surface expression as compared with the wild-type (WT) receptor. Although the hormone binding characteristics were similar to the WT receptor, its signaling activity was distinctly higher at lower dose of FSH as monitored by a cAMP assay. On the other hand, the mutant receptor 575 showed lower cell surface expression and higher internalized hormone receptor complex. Additionally, a dose-dependent increase in the cAMP accumulation was not observed in the case of this mutant as compared with WT.
Conclusion:
OHSS and primary amenorrhea observed in the two affected women, respectively, could be attributed to the functional characteristics of respective mutant FSHR.
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| 25653165 |
Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting |
10.1093/nar/gkv068. |
Nucleic Acids Res |
Structural and functional characterization of a cell cycle associated HDAC1/2 complex reveals the structural basis for complex assembly and nucleosome targeting
Abstract
- Recent proteomic studies have identified a novel histone deacetylase complex that is upregulated during mitosis and is associated with cyclin A. This complex is conserved from nematodes to man and contains histone deacetylases 1 and 2, the MIDEAS corepressor protein and a protein called DNTTIP1 whose function was hitherto poorly understood. Here, we report the structures of two domains from DNTTIP1. The amino-terminal region forms a tight dimerization domain with a novel structural fold that interacts with and mediates assembly of the HDAC1:MIDEAS complex. The carboxy-terminal domain of DNTTIP1 has a structure related to the SKI/SNO/DAC domain, despite lacking obvious sequence homology. We show that this domain in DNTTIP1 mediates interaction with both DNA and nucleosomes. Thus, DNTTIP1 acts as a dimeric chromatin binding module in the HDAC1:MIDEAS corepressor complex.
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