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21.
Gaucher disease-associated glucocerebrosidases show mutation-dependent chemical chaperoning profiles
Sawkar AR Adamski-Werner SL Cheng WC Wong CH Beutler E Zimmer KP Kelly JW 《Chemistry & biology》2005,12(11):1235-1244
Gaucher disease is a lysosomal storage disorder caused by deficient glucocerebrosidase activity. We have previously shown that the cellular activity of the most common Gaucher disease-associated glucocerebrosidase variant, N370S, is increased when patient-derived cells are cultured with the chemical chaperone N-nonyl-deoxynojirimycin. Chemical chaperones stabilize proteins against misfolding, enabling their trafficking from the endoplasmic reticulum. Herein, the generality of this therapeutic strategy is evaluated with other glucocerebrosidase variants and with additional candidate chemical chaperones. Improved chemical chaperones are identified for N370S glucocerebrosidase. Moreover, we demonstrate that G202R, a glucocerebrosidase variant that is known to be retained in the endoplasmic reticulum, is also amenable to chemical chaperoning. The L444P variant is not chaperoned by any of the active site-directed molecules tested, likely because this mutation destabilizes a domain distinct from the catalytic domain. 相似文献
22.
Spherical Cryptates. Synthesis and Inclusion-Complexes of Spherical Macrotricyclic Ligands A general strategy for the synthesis of spherical macrotricyclic ligands has been developed. Four spherical cryptands, SC - 24 , SC - 25 , SC - 26 and SC - 27 have been obtained by this route. The synthesis and cation-complexing properties of these compounds are described in detail. Stability constants and cation exchange rates of the spherical cryptates obtained with alkali and alkaline-earth cations have been determined. Highly stable complexes are formed by SC - 24 ; the Rb+ and Cs+ cryptates of SC - 24 are the most stable complexes of these cations known to date. The size of the intramolecular cavity affects the complexation selectivity. The cation exchange rates are very slow, and the corresponding free energies of activation are even larger than, for macrobicyclic cryptates of similar stability. Both the high complex stabilities and the high activation energies required for cation exchange indicate a marked ‘spherical cryptate effect’ resulting from the highly connected nature of the molecular architecture of spherical macrotricyclic ligands. 相似文献
23.
Capon RJ Skene C Liu EH Lacey E Gill JH Heiland K Friedel T 《Natural product research》2004,18(4):305-309
Bioassay directed fractionation of a Raspailia (Raspailia) sp. (Order Poecilosclerida; Family Raspailiidae) collected during scientific trawling operations off the Northern Rottnest Shelf yielded as nematocidal agents the known metabolites, phorboxazoles A (1) and B (2). Further examination revealed the new natural product but known synthetic compound, esmodil (3). The structure for 3 was confirmed by spectroscopic analysis and total synthesis. 相似文献
24.
Ernest Giralt Miguel Feliz Mario Rubiralta Joan Bosch 《Journal of heterocyclic chemistry》1984,21(3):715-720
Carbon-carbon sp3-sp2 rotational barriers of 3,3-dimethyl-2-(3,4,5-trimethoxyphenyl)-4-piperidones and their ethylene ketals have been evaluated using nmr techniques. The conformation of 1 hydrochloride has been studied by NOE determinations. Values found for the hydrochlorides of the title compounds are discussed in terms of equilibria with free bases and nitrogen inversion. 相似文献
25.
26.
Salvador Guardiola Monica Varese Xavier Roig Macarena Snchez-Navarro Jesús García Ernest Giralt 《Chemical science》2021,12(14):5164
Peptides are a rapidly growing class of therapeutics with various advantages over traditional small molecules, especially for targeting difficult protein–protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing bioactive cyclic topologies that go beyond natural l-amino acids. Here, we report a generalizable framework that exploits the computational power of Rosetta, in terms of large-scale backbone sampling, side-chain composition and energy scoring, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we developed two new inhibitors (PD-i3 and PD-i6) of programmed cell death 1 (PD-1), a key immune checkpoint in oncology. A comprehensive biophysical evaluation was performed to assess their binding to PD-1 as well as their blocking effect on the endogenous PD-1/PD-L1 interaction. Finally, NMR elucidation of their in-solution structures confirmed our de novo design approach. In silico design of heterochiral cyclic peptides that bind to a specific surface patch on the target protein (PD-1, in this case) and disrupt protein–protein interactions. 相似文献
27.
Dehestani A Lam WH Hrovat DA Davidson ER Borden WT Mayer JM 《Journal of the American Chemical Society》2005,127(10):3423-3432
Osmium tetroxide is reduced by molecular hydrogen in the presence of ligands in both polar and nonpolar solvents. In CHCl3 containing pyridine (py) or 1,10-phenanthroline (phen), OsO4 is reduced by H2 to the known Os(VI) dimers L2Os(O)2(mu-O)2Os(O)2L2 (L2 = py2, phen). However, in the absence of ligands in CHCl3 and other nonpolar solvents, OsO4 is unreactive toward H2 over a week at ambient temperatures. In basic aqueous media, H2 reduces OsO4(OH)n(n-) (n = 0, 1, 2) to the isolable Os(VI) complex, OsO2(OH)4(2-), at rates close to that found in py/CHCl3. Depending on the pH, the aqueous reactions are exergonic by deltaG = -20 to -27 kcal mol(-1), based on electrochemical data. The second-order rate constants for the aqueous reactions are larger as the number of coordinated hydroxide ligands increases, k(OsO4) = 1.6(2) x 10(-2) M(-1) s(-1) < k(OsO4(OH)-) = 3.8(4) x 10(-2) M(-1) s(-1) < k(OsO4(OH)2(2-)) = 3.8(4) x 10(-1) M(-1) s(-1). The observation of primary deuterium kinetic isotope effects, k(H2)/k(D2) = 3.1(3) for OsO4 and 3.6(4) for OsO4(OH)-, indicates that the rate-determining step in each case involves H-H bond cleavage. Density functional calculations and thermochemical arguments favor a concerted [3+2] addition of H2 across two oxo groups of OsO4(L)n and argue against H* or H- abstraction from H2 or [2+2] addition of H2 across one Os=O bond. The [3+2] mechanism is analogous to that of alkene addition to OsO4(L)n to form diolates, for which acceleration by added ligands has been extensively documented. The observation that ligands also accelerate H2 addition to OsO4(L)n highlights the analogy between these two reactions. 相似文献
28.
Pierre-Jean Madec Ernest Marechal 《Journal of polymer science. Part A, Polymer chemistry》1978,16(12):3157-3163
Block copolycondensates containing both unsaturated polyester and polysiloxane blocks have been prepared by copolycondensation of reactive oligomers; the bonds between the blocks are either Si? O? C or Si? C. This article is devoted to poly(ethylene adipate-co-maleate-b-siloxane) with Si? O? C bonds. The reactive oligomers are studied, before or after modification, by tonometry, end-group titration, GPC, and NMR. Contrary to the block copolycondensates of the same kind described in the literature, those reported in this work have high molecular weights (five block of each kind). These high-molecular-weight block polycondensates have been obtained by a careful study of the parameters of the polycondensation. 相似文献
29.
Monitoring of ethanol during fermentation using a microbial biosensor with enhanced selectivity 总被引:1,自引:0,他引:1
Tkac J Vostiar I Gemeiner P Sturdik E 《Bioelectrochemistry (Amsterdam, Netherlands)》2002,56(1-2):127-129
The present study is concerning the construction of ferricyanide-mediated Gluconobacter oxydans cell ethanol biosensor. The size exclusion effect of a cellulose acetate membrane was used for elimination of glucose interferences during ethanol assays in real samples. A typical response time of the biosensor was 13 s with a high sensitivity of 3.5 microA mM(-1). The microbial biosensor exhibits a very low detection limit of 0.85 microM and a wide linear range from 2 to 270 microM. The operational stability was excellent. During 8.5 h of repetitive ethanol assays, no decrease in the sensor sensitivity was observed. The biosensor was successfully used in the off-line monitoring of ethanol fermentation with a good agreement with HPLC measurements (R(2)=0.998). 相似文献
30.
Polymerase chain reaction techniques for food allergen detection 总被引:5,自引:0,他引:5
Food allergies represent an important health problem in industrialized countries. Undeclared allergenic foods as contaminants in food products pose a major risk for sensitized persons. Reliable detection and quantification methods for food allergens are necessary to ensure compliance with food labeling and improve consumer protection. The methods currently used for the detection of potential allergens in foods are to target either the allergen itself or a marker that indicates the presence of the offending food. As markers for the presence of potentially allergenic foods or ingredients, specific proteins or DNA fragments are targeted. In routine food analysis, the enzyme-linked immunosorbent assay (ELISA) and the polymerase chain reaction (PCR) in the form of a real-time PCR or in combination with an ELISA have been used. The availability, the characteristics, and some future aspects of DNA-based methods in the rapid and sensitive detection of potentially allergenic food constituents or contaminations are discussed in this review. 相似文献