| 24715439 |
Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals. |
10.1002/ajmg.a.36542 |
Am. J. Med. Genet. |
Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals.
Abstract
- Haploinsufficiency of HDAC4 gene has been reported to result in brachydactyly-"mental retardation" syndrome (BDMR), a condition with significant intellectual impairment, brachydactyly type E, and typical facial features. Presented here are three individuals with haploinsufficiency of HDAC4 who have brachydactyly type E, non-dysmorphic facial features, and normal intelligence. This is in contradistinction to previous reports that haploinsufficiency of HDAC4 is sufficient to cause BDMR.
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| 24727324 |
A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer |
10.1158/1078-0432.CCR-13-2686. |
Clin Cancer Res |
A phase I trial of LY2510924, a CXCR4 peptide antagonist, in patients with advanced cancer
Abstract
- Overexpression of C-X-C motif receptor 4 (CXCR4) is implicated in tumor progression. LY2510924 is a peptide antagonist, which blocks stromal cell-derived factor-1 (SDF1) from CXCR4 binding.
This phase I study included two parts: a 3+3 dose escalation (part A) and dose confirmation (part B). LY2510924 was administered as a daily subcutaneous injection on a 28-day cycle. The primary objective was to determine the recommended phase II dose. Secondary objectives included safety, pharmacokinetics, efficacy, and pharmacodynamic response, including mobilization of CD34(+) hematopoietic stem cells into the peripheral blood.
Forty-five patients were enrolled, 25 in part A and 20 in part B. Patients were administered increasing doses of LY2510924: 1.0, 2.5, 5.0, 10, 20, and 30 mg/day for part A and 2.5 or 20 mg/day for part B. Two patients (30-mg/day cohort) experienced dose-limiting toxicities of grade 3 increased neutrophil count. The maximum tolerated dose (MTD) was 20 mg/day. The most common drug-related treatment-emergent adverse events were fatigue (9%), injection-site reaction (9%), injection site pruritus (7%), and nausea (7%). The best response was stable disease for nine patients (20%). At the end of cycle 1, mean peak LY2510924 plasma concentration and the 24-hour area under the plasma concentration versus time curve increased slightly more than dose proportionally. LY2510924 dose dependently increased CD34(+) cell counts in peripheral blood up to 18-fold.
LY2510924 demonstrated CD34(+) cell mobilization at doses ≥2.5 mg/day with a tolerable safety profile up to an MTD of 20 mg/day.
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| 24742254 |
Cyclohexadepsipeptides of the isaridin class from the marine-derived fungus Beauveria felina EN-135 |
10.1021/np4011037. |
J Nat Prod |
Cyclohexadepsipeptides of the isaridin class from the marine-derived fungus Beauveria felina EN-135
Abstract
- Three new cyclohexadepsipeptides of the isaridin class including isaridin G (1), desmethylisaridin G (2), and desmethylisaridin C1 (3), along with three related known metabolites (4-6), were isolated and identified from the marine bryozoan-derived fungus Beauveria felina EN-135. The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, and the structures and absolute configurations of compounds 1-3 were confirmed by single-crystal X-ray diffraction analysis. The crystal structures showed the presence of β-turns for the Tyr(3)/N-Me-Val(4) and Phe(3)/N-Me-Val(4) amide bonds in compounds 2 and 3, respectively, in the cis conformations, which were opposite other reported isaridins. The conformations of the HMPA(1)-Pro(2) amide bond in compound 2 are different in the solution and in the crystal structures, which showed trans and cis geometries, respectively, while compounds 1 and 3 do not exhibit this phenomenon. Each of the isolated compounds was evaluated for antimicrobial activity and brine shrimp lethality. Compound 3 exhibited antibacterial activity against E. coli with an MIC value of 8 μg/mL.
|
| 24793743 |
Treatment of Troglostrongylus brevior (Metastrongyloidea, Crenosomatidae) in mixed lungworm infections using spot-on emodepside |
10.1177/1098612X14533552. |
J Feline Med Surg |
Treatment of Troglostrongylus brevior (Metastrongyloidea, Crenosomatidae) in mixed lungworm infections using spot-on emodepside
Abstract
- Feline lungworms have long been known as pathogens of cats. However, an increased incidence of clinical cases in some areas has been the focus of a number of recent epidemiological and clinical studies. While Aelurostrongylus abstrusus causes respiratory signs in cats all over the world, Troglostrongylus brevior has recently been found in domestic cats from Spain and Italy (where it often causes severe clinical signs). Capillaria aerophila, a parasite that infects many wild carnivores, may cause respiratory distress in cats. A variety of treatment options are known for A abstrusus, while almost no information is available on the treatment of troglostrongylosis and capillariosis. This series describes two mixed infections in clinically affected kittens with T brevior, one with concurrent A abstrusus and the other with C aerophila. In both cases, the nematodes were identified and confirmed by copromicroscopic examination and specific DNA-based assays. Kittens showed respiratory signs that resolved after one or two administrations of a spot-on solution containing emodepside. Larval (T brevior and A abstrusus) and egg (C aerophila) shedding was also eliminated 2-4 weeks after treatment. New clinical insights into these parasitoses are discussed.
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| 24813731 |
Total synthesis and antiplasmodial activity of pohlianin C and analogues |
10.1016/j.bmcl.2014.04.071. |
Bioorg Med Chem Lett |
Total synthesis and antiplasmodial activity of pohlianin C and analogues
Abstract
- The first synthesis of the glycine-rich cyclic octapeptide pohlianin C is reported, confirming the structure of this natural product. Screening against Plasmodium falciparum reveals moderate antiplasmodial activity, consistent with data obtained from the natural sample. In addition, the synthesis of three analogues reveals that the antiplasmodial activity of pohlianin C can be preserved or increased with simplified structures.
|
| 24828289 |
Cyclodepsipeptides and other O-containing heterocyclic metabolites from Beauveria felina EN-135, a marine-derived entomopathogenic fungus |
10.3390/md12052816. |
Mar Drugs |
Cyclodepsipeptides and other O-containing heterocyclic metabolites from Beauveria felina EN-135, a marine-derived entomopathogenic fungus
Abstract
- Bioassay-guided fractionation of a culture extract of Beauveria felina EN-135, an entomopathogenic fungus isolated from a marine bryozoan, led to the isolation of a new cyclodepsipeptide, iso-isariin D (1); two new O-containing heterocyclic compounds that we have named felis A and B (2 and 3); and four known cyclodepsipeptides (4-7). The structures were elucidated via spectroscopic analysis, and the absolute configurations of 1 and 2 were determined using single-crystal X-ray diffraction and CD, respectively. All isolated compounds were evaluated for antimicrobial activity and brine-shrimp (Artemia salina) lethality.
|
| 24841822 |
Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus |
10.1016/j.fgb.2014.04.011. |
Fungal Genet Biol |
Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus
Abstract
- Ustiloxin B is a secondary metabolite known to be produced by Ustilaginoidea virens. In our previous paper, we observed the production of this compound by Aspergillus flavus, and identified two A. flavus genes responsible for ustiloxin B biosynthesis (Umemura et al., 2013). The compound is a cyclic tetrapeptide of Tyr-Ala-Ile-Gly, whose tyrosine is modified with a non-protein coding amino acid, norvaline. Although its chemical structure strongly suggested that ustiloxin B is biosynthesized by a non-ribosomal peptide synthetase, in the present study, we observed its synthesis through a ribosomal peptide synthetic (RiPS) pathway by precise sequence analyses after experimental validation of the cluster. The cluster possessed a gene (AFLA_094980), termed ustA, whose translated product, UstA, contains a 16-fold repeated peptide embedding a tetrapeptide, Tyr-Ala-Ile-Gly, that is converted into the cyclic moiety of ustiloxin B. This result strongly suggests that ustiloxin B is biosynthesized through a RiPS pathway and that UstA provides the precursor peptide of the compound. The present work is the first characterization of RiPS in Ascomycetes and the entire RiPS gene cluster in fungi. Based on the sequence analyses, we also proposed a biosynthetic mechanism involving the entire gene cluster. Our finding indicates the possibility that a number of unidentified RiPSs exist in Ascomycetes as the biosynthetic genes of secondary metabolites, and that the feature of a highly repeated peptide sequence in UstA will greatly contribute to the discovery of additional RiPS.
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| 24848421 |
Identification of a gene cluster responsible for the biosynthesis of cyclic lipopeptide verlamelin |
10.1007/s00253-014-5803-7. |
Appl Microbiol Biotechnol |
Identification of a gene cluster responsible for the biosynthesis of cyclic lipopeptide verlamelin
Abstract
- Only limited studies are available on the molecular-level biosynthesis of cyclic lipopeptides (cyclic and hybrid molecules consisting of peptide and fatty acid moieties) in filamentous fungi. Here, we identified and characterized biosynthetic genes of the cyclic lipopeptides, known as verlamelins. Only four genes, coding for non-ribosomal peptide synthetase (NRPS), fatty acid hydroxylase, thioesterase, and AMP-dependent ligase, were found to be involved in verlamelin biosynthesis by the analysis of corresponding gene knockouts. Surprisingly, no gene(s) coding for fatty acid synthase or polyketide synthase was present in the cluster, while verlamelin A/B contained a 5-hydroxytetradecanoic acid moiety. Precursor feeding experiment indicated that both fatty acid hydroxylase and thioesterase are involved to supply 5-hydroxytetradecanoic acid. The results suggested that 5-hydroxytetradecanoic acid was supplied from primary metabolism via fatty acid hydroxylase and loaded onto NRPS. Elongation of the peptide and final cyclization were accomplished by NRPS. The knowledge obtained through this study should provide new insight into fungal lipopeptide biosynthesis.
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| 24848423 |
Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A |
10.1002/anie.201403071. |
Angew Chem Int Ed Engl |
Stereoselective fluorination alters the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues of unguisin A
Abstract
- New methods for enhancing the efficiency of peptide cyclization, and for fine-tuning the conformations of cyclic peptides, are valuable from a drug development perspective. Herein stereoselective fluorination is investigated as a new strategy for achieving these goals. Four vicinal difluorinated analogues of the natural cyclic heptapeptide unguisin A have been efficiently synthesized. The analogues are found to adopt dramatically different secondary structures, controlled by the fluorine stereochemistry.
|
| 24868880 |
Two peptides, cycloaspeptide A and nazumamide A from a sponge associated marine actinobacterium Salinispora sp |
None |
Nat Prod Commun |
Two peptides, cycloaspeptide A and nazumamide A from a sponge associated marine actinobacterium Salinispora sp
Abstract
- Marine sponges are a major component of benthic communities and act as a reservoir for microbial species. In terms of biomass, they are the richest source of secondary metabolite production, with the potential to influence both benthic and pelagic systems. In most cases it is the sponge-associated microbes that account for many of the secondary metabolites assigned to the host. Here we report the occurrence of cycloaspeptide A, a fungus-derived cyclic peptide, in a culturable bacterium Salinispora arenicola. We have also identified nazumamide A, a sponge-derived linear tetrapeptide currently used as a thrombin inhibitor, in Salinispora pacifica. Their structures were determined using an integrated approach consisting of: (1) HPLC-UV-Vis-QToF-MS analysis with multimode ionization (ESI and APCI) and fast polarity switching; (2) database searching and matching of monoisotopic masses, retention times, mass spectra of the precursor and product ions of the compounds of interest and the authentic reference standards thereof.
|
| 24878223 |
Molecular phylogeny and evolution of the cone snails (Gastropoda, Conoidea) |
10.1016/j.ympev.2014.05.023. |
Mol Phylogenet Evol |
Molecular phylogeny and evolution of the cone snails (Gastropoda, Conoidea)
Abstract
- We present a large-scale molecular phylogeny that includes 320 of the 761 recognized valid species of the cone snails (Conus), one of the most diverse groups of marine molluscs, based on three mitochondrial genes (COI, 16S rDNA and 12S rDNA). This is the first phylogeny of the taxon to employ concatenated sequences of several genes, and it includes more than twice as many species as the last published molecular phylogeny of the entire group nearly a decade ago. Most of the numerous molecular phylogenies published during the last 15years are limited to rather small fractions of its species diversity. Bayesian and maximum likelihood analyses are mostly congruent and confirm the presence of three previously reported highly divergent lineages among cone snails, and one identified here using molecular data. About 85% of the species cluster in the single Large Major Clade; the others are divided between the Small Major Clade (∼12%), the Conus californicus lineage (one species), and a newly defined clade (∼3%). We also define several subclades within the Large and Small major clades, but most of their relationships remain poorly supported. To illustrate the usefulness of molecular phylogenies in addressing specific evolutionary questions, we analyse the evolution of the diet, the biogeography and the toxins of cone snails. All cone snails whose feeding biology is known inject venom into large prey animals and swallow them whole. Predation on polychaete worms is inferred as the ancestral state, and diet shifts to molluscs and fishes occurred rarely. The ancestor of cone snails probably originated from the Indo-Pacific; rather few colonisations of other biogeographic provinces have probably occurred. A new classification of the Conidae, based on the molecular phylogeny, is published in an accompanying paper.
|
| 24891254 |
Incrementally increasing the length of a peptide backbone: effect on macrocyclisation efficiency |
10.1039/c4ob00492b. |
Org Biomol Chem |
Incrementally increasing the length of a peptide backbone: effect on macrocyclisation efficiency
Abstract
- Three novel analogues of the cyclic pentapeptide sansalvamide A have been synthesised in high yield. A leucine residue in the lead compound is replaced with either a glycine, β-alanine or GABA residue, and the corresponding linear precursor peptides are found to cyclise with dramatically improved efficiency. This correlates with an increase in the effective molarity (EM) of the cyclisation reactions.
|
| 24917937 |
Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation |
10.1177/2050640612474446. |
United European Gastroenterol J |
Linaclotide: A new drug for the treatment of chronic constipation and irritable bowel syndrome with constipation
Abstract
- Linaclotide is the first member of a novel class of drugs to be extensively evaluated for the treatment of chronic constipation (CC) and irritable bowel syndrome with constipation (IBS-C).
To provide a comprehensive overview of the current state of knowledge on linaclotide, its pharmacological properties, mode of action and efficacy in clinical trials to date.
We conducted a systematic review of the literature.
The survey revealed that linaclotide is a minimally absorbed, 14-amino acid peptide which acts in the intestinal lumen on guanylate cyclase-C (GC-C). This results in generation of cyclic guanosine monophosphate (cGMP), which stimulates chloride secretion, resulting in increased luminal fluid secretion and an acceleration of intestinal transit. In animal models, linaclotide also decreased visceral hypersensitivity. Linaclotide softened stool and increased transit in CC and in IBS-C. Phase II and phase III clinical studies established efficacy of linaclotide in CC (linaclotide 145 µg daily approved in the United States for CC) and in IBS-C (linaclotide 290 µg daily US Food and Drug Administration-approved for IBS-C, with favourable recommendation for the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). Linaclotide showed a favourable safety profile, and the main treatment-emerging adverse event was diarrhea, leading to discontinuation rates of up to 5%. Linaclotide is an important addition to the therapeutic possibilities for treating IBS-C and CC.
|
| 24918360 |
Microcystins alter chemotactic behavior in Caenorhabditis elegans by selectively targeting the AWA sensory neuron |
10.3390/toxins6061813. |
Toxins (Basel) |
Microcystins alter chemotactic behavior in Caenorhabditis elegans by selectively targeting the AWA sensory neuron
Abstract
- Harmful algal blooms expose humans and animals to microcystins (MCs) through contaminated drinking water. While hepatotoxicity following acute exposure to MCs is well documented, neurotoxicity after sub-lethal exposure is poorly understood. We developed a novel statistical approach using a generalized linear model and the quasibinomial family to analyze neurotoxic effects in adult Caenorhabditis elegans exposed to MC-LR or MC-LF for 24 h. Selective effects of toxin exposure on AWA versus AWC sensory neuron function were determined using a chemotaxis assay. With a non-monotonic response MCs altered AWA but not AWC function, and MC-LF was more potent than MC-LR. To probe a potential role for protein phosphatases (PPs) in MC neurotoxicity, we evaluated the chemotactic response in worms exposed to the PP1 inhibitor tautomycin or the PP2A inhibitor okadaic acid for 24 h. Okadaic acid impaired both AWA and AWC function, while tautomycin had no effect on function of either neuronal cell type at the concentrations tested. These findings suggest that MCs alter the AWA neuron at concentrations that do not cause AWC toxicity via mechanisms other than PP inhibition.
|
| 24943257 |
Production of scopularide A in submerged culture with Scopulariopsis brevicaulis |
10.1186/1475-2859-13-89. |
Microb Cell Fact |
Production of scopularide A in submerged culture with Scopulariopsis brevicaulis
Abstract
- Marine organisms produce many novel compounds with useful biological activity, but are currently underexploited. Considerable research has been invested in the study of compounds from marine bacteria, and several groups have now recognised that marine fungi also produce an interesting range of compounds. During product discovery, these compounds are often produced only in non-agitated culture conditions, which are unfortunately not well suited for scaling up. A marine isolate of Scopulariopsis brevicaulis, strain LF580, produces the cyclodepsipeptide scopularide A, which has previously only been produced in non-agitated cultivation.
Scopulariopsis brevicaulis LF580 produced scopularide A when grown in batch and fed-batch submerged cultures. Scopularide A was extracted primarily from the biomass, with approximately 7% being extractable from the culture supernatant. By increasing the biomass density of the cultivations, we were able to increase the volumetric production of the cultures, but it was important to avoid nitrogen limitation. Specific production also increased with increasing biomass density, leading to improvements in volumetric production up to 29-fold, compared with previous, non-agitated cultivations. Cell densities up to 36 g L-1 were achieved in 1 to 10 L bioreactors. Production of scopularide A was optimised in complex medium, but was also possible in a completely defined medium.
Scopularide A production has been transferred from a non-agitated to a stirred tank bioreactor environment with an approximately 6-fold increase in specific and 29-fold increase in volumetric production. Production of scopularide A in stirred tank bioreactors demonstrates that marine fungal compounds can be suitable for scalable production, even with the native production organism.
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