Designed helical peptides inhibit an intramembrane protease

gamma-Secretase cleaves the transmembrane domain of the amyloid precursor protein, a process implicated in the pathogenesis of Alzheimer's disease, and this enzyme is a founding member of an emerging class of intramembrane proteases. Modeling and mutagenesis suggest a helical conformation for the substrate transmembrane domain upon initial interaction with the protease. Moreover, biochemical evidence supports the presence of an initial docking site for substrate on gamma-secretase that is distinct from the active site, a property predicted to be generally true of intramembrane proteases. Here we show that short peptides designed to adopt a helical conformation in solution are inhibitors of gamma-secretase in both cells and enzyme preparations. Helical peptides with all d-amino acids are the most potent inhibitors and represent potential therapeutic leads. Subtle modifications that disrupt helicity also substantially reduce potency, suggesting that this conformation is critical for effective inhibition. Fluorescence lifetime imaging in intact cells demonstrates that helical peptides disrupt binding between substrate and protease, whereas an active site-directed inhibitor does not. These findings are consistent with helical peptides interacting with the initial substrate docking site of gamma-secretase, suggesting a general strategy for the development of potent and specific inhibitors of intramembrane proteases.     

The formylation of the upper-rims of thiacalixarenes: synthesis of the first tetra-formylated and the first meta-substituted thiacalix[4]arenes

The conventional Gross reaction for the formylation of the tetrapropoxythiacalix[4]arene using TiCl₄ affords the 18-(chloromethyl)-28-hydroxy-25,26,27-tripropoxythiacalix[4]arene substituted in the meta-position of the macrocycle. The p-tetraformyl-tetrapropoxythiacalix[4]arene, which is an interesting intermediate to the upper-rims functionalization of thiacalixarenes, was prepared with a very good yield using BuLi and N-formylpiperidine.     

qNMR for profiling the production of fungal secondary metabolites

Analysis of complex mixtures is a common challenge in natural products research. Quantitative nuclear magnetic resonance spectroscopy offers analysis of complex mixtures at early stages and with benefits that are orthogonal to more common methods of quantitation, including ultraviolet absorption spectroscopy and mass spectrometry. Several experiments were conducted to construct a methodology for use in analysis of extracts of fungal cultures. A broadly applicable method was sought for analysis of both pure and complex samples through use of an externally calibrated method. This method has the benefit of not contaminating valuable samples with the calibrant, and it passed scrutiny for line fitting and reproducibility. The method was implemented to measure the yield of griseofulvin and dechlorogriseofulvin from three fungal isolates. An isolate of Xylaria cubensis (coded MSX48662) was found to biosynthesize griseofulvin in the greatest yield, 149 ± 8 mg per fermentation, and was selected for further supply experiments. Copyright © 2016 John Wiley & Sons, Ltd.     

Rheological Behavior and Non-enzymatic Degradation of a Sulfated Galactan from Halymenia durvillei (Halymeniales, Rhodophyta)

The rheological behavior of a sulfated galactan extracted from Halymenia durvillei, a red seaweed collected in the coastal waters of a small island of Madagascar (Nosy-be in Indian Ocean), was investigated in dilute and semi-dilute solutions. In dilute solution with NaCl at 0.3?M, the polysaccharide adopted a coil conformation whereas, at higher concentrations, the polymer had the behavior of shear-thinning fluid, typical of polymer with high molar mass or semi-rigid conformation. Degradations of this lambda carrageenan-like, using radical depolymerization, and high-pressure homogenization led to several samples of various and controlled molar masses. The measure of their intrinsic viscosities permitted the determination of the relationship of Mark?CHouwink?CSakurada.     

Highly efficient metal‐free organic catalysts to design new Environmentally‐friendly starch‐based blends

A one‐step process is reported to directly synthesize blends of poly(trimethylene carbonate) (PTMC) with a modified granular starch. Trimethylene Carbonate (TMC) ring‐opening polymerization is performed in the presence of native starch particles in bulk conditions at 150 °C and the efficiency of metal‐free organic catalysts (TBD and phosphazene superbases P1‐t‐Oct, P2‐t‐bu, and P4‐t‐bu) are investigated to replace the organo‐metallic stannous octanoate initiator. TMC monomer is successively converted into PTMC and the robustness of organic catalysts is highlighted with significant activities at very low concentrations (<100 ppm), where stannous octanoate is inefficient. Reactivity of starch toward TMC ROP is deeply investigated by NMR techniques and a starch‐graft‐PTMC is indirectly evidenced. Starch substitution degree reaches 0.9% indicating that PTMC grafting only occurs at the surface of swollen granular starch. PTMC graft length from the starch surface remained low in the range 2–12 and model ROP reactions highlight the role of TMC hydrolysis on PTMC graft length. Despite low PTMC grafts, a fine dispersion of intact starch particles into the PTMC matrix is evidenced. Consequently, metal‐free organic catalysts at low concentrations are promising candidates for synthesizing blends of PTMC with high loadings of surface‐modified starch (32% by weight) in 2 min within a one‐step process. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 493–503     

Induced Production,Synthesis, and Immunomodulatory Action of Clostrisulfone,a Diarylsulfone from Clostridium acetobutylicum

The anaerobe Clostridium acetobutylicum belongs to the most important industrially used bacteria. Whereas genome mining points to a high potential for secondary metabolism in C. acetobutylicum, the functions of most biosynthetic gene clusters are cryptic. We report that the addition of supra-physiological concentrations of cysteine triggered the formation of a novel natural product, clostrisulfone ( 1 ). Its structure was fully elucidated by NMR, MS and the chemical synthesis of a reference compound. Clostrisulfone is the first reported natural product with a diphenylsulfone scaffold. A biomimetic synthesis suggests that pentamethylchromanol-derived radicals capture sulfur dioxide to form 1 . In a cell-based assay using murine macrophages a biphasic and dose-dependent regulation of the LPS-induced release of nitric oxide was observed in the presence of 1 .     

The Synthesis of a γ-Keto-α-amino Acid,a Key Intermediate in the Synthesis of Monatin,a New Natural Sweetener

An efficient method was developed for the synthesis of the ketoamino acid 2, a key intermediate in the synthesis of the novel sweet compound, monatin 1. Preparation of 2 entails coupling of a suitably protected indole acetate anion to an aspartic acid derivative.     

An Efficient Synthesis of Dicarbonyl (η5—Cyclopentadien—YL)Iron(II) Complexes of Two Cyclic Enol Ethers

An efficient synthesis of dicarbonyl(η⁵—cyclopentadienyl)iron—(II)—complexes of 2,3—dihydrofuran and 3,4—dihydro—2H—pyran from 3—bromo—2—methoxytetrahydrofuran and—pyran, respectively, is described.     

The total synthesis of 13(R)- and 13(S)-dihydro-4-demethoxy-daunorubicin. Revision of stereochemistry of the microbial and mammalian reduction product of 4-demethoxydaunorubicin

The properties of 13(S)-dihydro-4-demethoxydaunorubicin, rather than the 13(R)-isomer, correspond to those of the microbial and mammalian reduction product of 4-demethoxydauno-rubicin.     

Femtosecond laser fabrication of tubular waveguides in poly(methyl methacrylate)

Femtosecond laser direct writing is employed for the fabrication of buried tubular waveguides in bulk poly(methyl methacrylate). A novel technique using selective chemical etching is presented to resolve the two-dimensional refractive-index profile of the fabrication structures. End-to-end coupling in the waveguides reveals a near-field intensity distribution that results from the superimposition of several propagating modes with different azimuthal symmetries. Mode analysis of the tubular waveguides is performed using the finite-difference method, and the possible propagating mode profiles are compared with the experimental data.