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11.
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
12.
Herein, we report a stereospecific E-olefin dipeptide isostere synthesis that can be used to make gram quantities of the Phe-Phe isostere desired for eliminating a specific backbone H-bond donor and acceptor in the Alzheimer's disease related Abeta peptide. The Phe19-Phe20 E-olefin analogue of Abeta(1-40) was prepared by solid-phase peptide synthesis and was subjected to amyloidogenesis conditions. This analogue can aggregate into spherical morphologies but does not progress on to form protofibrils or fibrils as is the case for the all-amide sequence, providing insight into the structural requirements for amyloidogenesis. 相似文献
13.
Three new linear compounds of the type Co(3)(dpa)(4)X(2), where dpa is the anion of di(2-pyridyl)amine and X is NCS(-) (5), CN(-) (6), and N(CN)(2)(-) (7), have been prepared, and their structures and magnetic behavior have been studied. In all of them, including three different solvates of 5, the Co(3) chains are symmetrical with Co-Co distances of ca. 2.31-2.32 A. The appearance of four lines in the (1)H NMR spectra of the three compounds is also consistent with a symmetrical structure in solution. For all compounds, the magnetic behavior is quite similar with mu(eff) of ca. 1.9-2.0 micro(B) at temperatures between 1.8 and 200 K. As the temperature increases, the effective moments increase gradually, but since saturation is not reached, even at 400 K, the high-spin state cannot be assigned. 相似文献
14.
Deechongkit S Powers ET You SL Kelly JW 《Journal of the American Chemical Society》2005,127(23):8562-8570
Low molecular weight peptidomimetics with simple amphiphilic sequences can help to elucidate the structures of cross beta-sheet assemblies, such as amyloid fibrils. The peptidomimetics described herein comprise a dibenzofuran template, two peptide strands made up of alternating hydrophilic and hydrophobic residues, and carboxyl termini, each of which can be varied to probe the structural requirements for beta-sheet self-assembly processes. The dibenzofuran template positions the strands approximately 10 A apart, allowing corresponding hydrophobic side chains in the strands to pack into a collapsed U-shaped structure. This conformation is stabilized by hydrophobic interactions, not intramolecular hydrogen bonds. Intermolecular stacking of the collapsed peptidomimetics, enabled by intermolecular hydrogen bonding and hydrophobic interactions, affords 25-27 A wide protofilaments having a cross beta-sheet structure. Association of protofilaments, mediated by the dibenzofuran substructures and driven by the hydrophobic effect, affords 50-60 A wide filaments. These widths can be controlled by changing the length of the peptide strands. Further assembly of the filaments into fibrils or ribbons can be controlled by modification of the template, C-terminus, and buffer ion composition. 相似文献
15.
Desjardins A Flemming J Sternberg ED Dolphin D 《Chemical communications (Cambridge, England)》2002,(22):2622-2623
Protoporphyrin reacts with diazomethane to give pyrazolines which at long wavelength (approximately 630 nm) extrude nitrogen to give the corresponding cyclopropyl derivatives. 相似文献
16.
Jeffery B. Press Corris M. Hofmann Gretchen E. Wiegand Sidney R. Safir 《Journal of heterocyclic chemistry》1982,19(2):391-394
Pyrido[3,2-b]thieno[3,4-e][1,4]diazepines ( 1a-d ) were synthesized to investigate their potential CNS activity. Synthesis of the desired ring system was effected by condensation of 2,3-diaminopyridine ( 3 ) with methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 4 ). Structural assignment of the major condensation product 5 was determined by comparison of 1H nmr absorptions of 5 with those of related methyl lactam derivatives 11 and 14. A discussion of the possible mechanism leading to 5 in preference to isomeric lactam 6 is presented. Biological evaluation of 1a-d revealed no interesting properties. 相似文献
17.
Paul RL Argent SP Jeffery JC Harding LP Lynam JM Ward MD 《Dalton transactions (Cambridge, England : 2003)》2004,(21):3453-3458
Reaction of the bis-bidentate bridging ligand L(3), in which two bidentate chelating 3(2-pyridyl)pyrazole units are separated by a 3,3'-biphenyl spacer, with Co(II) salts affords tetranuclear cage complexes of composition [Co(4)(L(3))(6)]X(8)(X =[BF(4)](-), [ClO(4)](-), [PF(6)](-) or I(-)) in which four 6-coordinate Co(II) ions in an approximately tetrahedral array are connected by six bis-bidentate bridging ligands, one spanning each of the six edges of the Co(4) tetrahedron. In every case, X-ray crystallography reveals that the 'apical' Co(II) ion has a fac tris-chelate geometry, whereas the other three Co(II) ions have mer tris-chelate geometries, resulting in (non-crystallographic)C(3) symmetry for the cages; that this structure is retained in solution is confirmed by (1)H NMR spectroscopy of the paramagnetic cages. In every case one of the anions is located inside the central cavity of the cage, with the remaining seven outside. We found no clear evidence for an anion-based templating effect. The cage superstructure is sufficiently large to leave gaps in the centres of the faces through which the internal and external anions can exchange. Variable-temperature (19)F NMR spectroscopy was used to investigate the dynamic behaviour of the cages with X =[BF(4)](-) and [PF(6)](-) in MeCN solution: in both cases two separate signals, corresponding to external and internal anions, are clear at 233 K which have coalesced to a single signal at room temperature. Analysis of the linewidth of the minor signal (for the internal anion) at various temperatures below coalescence gave an activation energy for anion exchange of ca. 50 kJ mol(-1) in each case, a figure which suggests that anion exchange can occur via a conformational rearrangement of the cage superstructure in solution rather than opening of the cavity by cleavage of metal-ligand bonds. 相似文献
18.
Phosphazene rings with (dimethylamino)ethoxy (1, 2), pyridylmethoxy (3), or (dimethylamino)propoxy (4) chains were synthesized and quaternized at the substitutent nitrogen by treatment with methyl iodide at 35 degrees C over 3-6 h to give polyiodo salts, 5-8. Subsequent metathesis with LiN(SO(2)CF(3))(2) or NaBF(4) gave the respective ionic salts, 9-13. The amide salts, 9-12, were viscous liquids with pour points at 55-100 degrees C, and the tetrafluoroborate salt, 13, was a solid, mp 168 degrees C. The compositions of 2 and 5-13 were confirmed by elemental analysis and spectroscopic methods. Compounds 1, 2, and 4 were viscous liquids (d(25) = 1.67 g cm(-3); eta(25) = 0.76-1.56 mPa s(-1) ) with pour points at approximately 15 degrees C. The solid polyquaternary salts, 5-8, melted at 130-194 degrees C. The ionic liquids, 9-12, had an average density of approximately 1.73 g cm(-3) at 25 degrees C, and viscosities (25 degrees C) ranged between 68.3 and 139.2 mPa s(-1). A plot of the viscosities of 9-12 vs temperature revealed an almost linear correlation between 55 and 120 degrees C. Friction and wear properties of water with 0.25 wt % of 9-12 as boundary lubricant additives were evaluated on Si(3)N(4)/Si(3)N(4) ceramic interfaces. The most significant observation is that they caused a decrease in the running-in period. 相似文献
19.
Petrassi HM Johnson SM Purkey HE Chiang KP Walkup T Jiang X Powers ET Kelly JW 《Journal of the American Chemical Society》2005,127(18):6662-6671
Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1). An X-ray cocrystal structure of TTR.1(2) reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employed to append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramatically increased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on the native tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions. Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to ameliorate disease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventing the onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclear which of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enables these inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma, required for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-based amyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates for further pharmacologic evaluation. 相似文献
20.
We report direct experimental observation of local conformational dynamics in a polymer chain at the calorimetric glass transition temperature Tg. Variable-temperature two-dimensional (2D) solid-state exchange NMR, at natural abundance, reveals segmental dynamics in pure polyisobutylene (PIB) occurring on a time scale of several seconds over the Tg range observed by DSC (203-208 K). To our knowledge, this is the first direct observation of molecular-level conformer interchange (trans-trans/trans-gauche/gauche-gauche) at the caloric glass transition temperature. Our results provide a chronologically accurate and pedagogically advantageous demonstration of molecular processes during a polymer phase transition, relative to traditional bulk mechanical and calorimetric techniques. More importantly, we use a miscible blend to demonstrate a general strategy for quantitative evaluation of configurational entropy changes via combination of temperature-dependent 2D exchange NMR and Adams-Gibbs theory. Our results on the Tg time scale are directly relevant to fundamental understanding of the Tg length scale, i.e., the dimension of cooperatively rearranging regions. 相似文献