| 1. |
- Haugaard-Kedström, Linda M., et al.
(författare)
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Design, synthesis, and characterization of a single-chain peptide antagonist for the relaxin-3 receptor RXFP3
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:13, s. 4965-4974
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Tidskriftsartikel (refereegranskat)abstract
- Relaxin-3 is a two-chain disulfide-rich peptide that is the ancestral member of the relaxin peptide family and, together with its G protein-coupled receptor RXFP3, is highly expressed in the brain. Strong evolutionary conservation of relaxin-3 suggests a critical biological function and recent studies have demonstrated modulation of sensory, neuroendocrine, metabolic, and cognitive systems. However, detailed studies of central relaxin-3-RXFP3 signaling have until now been severely hampered by the lack of a readily available high-affinity antagonist for RXFP3. Previous studies have utilized a complex two-chain chimeric relaxin peptide, R3(B Delta 23-27)R/I5, in which a truncated relaxin-3 B-chain carrying an additional C-terminal Arg residue was combined with the insulin-like peptide S (INSL5) A-chain. In this study we demonstrate that, by replacing the native Cys in this truncated relaxin-3 B-chain with Ser, a single-chain linear peptide of 23 amino acids that retains high-affinity antagonism for RXFP3 can be achieved. In vivo studies demonstrate that this peptide, R3 B1-22R, antagonized relaxin-3/RXFP3 induced increases in feeding in rats after intracerebroventricular injection. Thus, R3 B1-22R represents an excellent tool for biological studies probing relaxin pharmacology and a lead molecule for the development of synthetically tractable, single-chain RXFP3 modulators for clinical use.
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| 2. |
- Karlsson, Björn C. G., et al.
(författare)
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Structure and Dynamics of Monomer-Template Complexation: An Explanation for Molecularly Imprinted Polymer Recognition Site Heterogeneity
- 2009
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 131:37, s. 13297-13304
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Tidskriftsartikel (refereegranskat)abstract
- We here present the first simulation of a complete molecularly imprinted polymer prepolymerization system. Molecular dynamics studies were performed for a system comprising a total of 1199 discrete molecules, replicating the components and concentrations employed in the corresponding polymer synthesis. The observed interactions correlate well with results obtained from (1)H NMR spectroscopic studies. Comparison with simulations performed in the absence of cross-linking agent (ethylene dimethacrylate) demonstrated its significance in the formation of ligand recognition sites. Moreover, the influence of events such as template-template (bupivacaine) and monomer-monomer (methacrylic acid) self-association, porogen-template interactions, and template conformational variability was revealed. The template recognition capacity of the modeled polymer system was verified by synthesis of imprinted and reference polymers and subsequent radioligand binding Analysis. Collectively, through a series of statistical analyses of molecular trajectories in conjunction with spectroscopic data it was demonstrated that an ensemble of complex structures is present in the prepolymerization mixture and that this diversity is the basis for the binding site heterogeneity observed in molecularly imprinted polymers (MIPs) prepared using the noncovalent strategy.
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| 3. |
- Liu, Yu, et al.
(författare)
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De Novo-Designed Enzymes as Small-Molecule-Regulated Fluorescence Imaging Tags and Fluorescent Reporters
- 2014
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 136:38, s. 13102-13105
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Tidskriftsartikel (refereegranskat)abstract
- Enzyme-based tags attached to a protein-of-interest (POI) that react with a small molecule, rendering the conjugate fluorescent, are very useful for studying the POI in living cells. These tags are typically based on endogenous enzymes, so protein engineering is required to ensure that the small-molecule probe does not react with the endogenous enzyme in the cell of interest. Here we demonstrate that de novo-designed enzymes can be used as tags to attach to POIs. The inherent bioorthogonality of the de novo-designed enzyme-small-molecule probe reaction circumvents the need for protein engineering, since these enzyme activities are not present in living organisms. Herein, we transform a family of de novo-designed retroaldolases into variable-molecular-weight tags exhibiting fluorescence imaging, reporter, and electrophoresis applications that are regulated by tailored, reactive small-molecule fluorophores.
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| 4. |
- Oruganti, Baswanth, et al.
(författare)
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Photoinduced Changes in Aromaticity Facilitate Electrocyclization of Dithienylbenzene Switches
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:32, s. 13941-13953
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Tidskriftsartikel (refereegranskat)abstract
- The concepts of excited-state aromaticity and antiaromaticity have in recent years with increasing frequency been invoked to rationalize the photochemistry of cyclic conjugated organic compounds, with the long-term goal of using these concepts to improve the reactivities of such compounds toward different photochemical transformations. In this regard, it is of particular interest to assess how the presence of a benzene motif affects photochemical reactivity, as benzene is well-known to completely change its aromatic character in its lowest excited states. Here, we investigate how a benzene motif influences the photoinduced electrocyclization of dithienylethenes, a major class of molecular switches. Specifically, we report on the synthesis of a dithienylbenzene switch where the typical nonaromatic, ethene-like motif bridging the two thienyl units is replaced by a benzene motif, and show that this compound undergoes electrocyclization upon irradiation with UV-light. Furthermore, through a detailed quantum chemical analysis, we demonstrate that the electrocyclization is driven jointly and synergistically by the loss of aromaticity in this motif from the formation of a reactive, antiaromatic excited state during the initial photoexcitation, and by the subsequent relief of this antiaromaticity as the reaction progresses from the Franck-Condon region. Overall, we conclude that photoinduced changes in aromaticity facilitate the electrocyclization of dithienylbenzene switches.
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| 5. |
- Ren, Yansong, et al.
(författare)
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Multistimuli-Responsive Enaminitrile Molecular Switches Displaying H+-Induced Aggregate Emission, Metal Ion-Induced Turn-On Fluorescence, and Organogelation Properties
- 2018
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 140:42, s. 13640-13643
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Tidskriftsartikel (refereegranskat)abstract
- Multistimuli-responsive enaminitrile-based configurational switches displaying aggregation-induced emission (AIE), fluorescence turn-on effects, and super gelation properties are presented. The E-isomers dominated (>97%) in neutral/basic solution, and the structures underwent precisely controlled switching around the enamine C=C bond upon addition of acid/base. Specific fluorescence output was observed in response to different external input in the solution and solid states. In response to H+, configurational switching resulted in complete formation of the nonemissive Z-H+-isomers in solution, however displaying deep-blue to blue fluorescence (Phi(F) up to 0.41) in the solid state. In response to Cu-II in the solution state, the E-isomers exhibited intense, turn-on, blue-green fluorescence, which could be turned off by addition of competitive coordination. The acid/base-activated switching, together with the induced AIE-effects, further enabled the accomplishment of a responsive superorganogelator. In nonpolar solvents, a blue-fluorescent supramolecular gel was formed upon addition of acid to the E-isomer suspension. The gelation could be reversed by addition of base, and the overall, reversible process could be repeated at least five cycles.
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| 6. |
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| 7. |
- Shinde, Sudhirkumar, et al.
(författare)
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Urea-Based Imprinted Polymer Hosts with Switchable Anion Preference
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:26, s. 11404-11416
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Tidskriftsartikel (refereegranskat)abstract
- The design of artificial oxyanion receptors with switchable ion preference is a challenging goal in host-guest chemistry. We here report on molecularly imprinted polymers (MIPs) with an external phospho-sulpho switch driven by small molecule modifiers. The polymers were prepared by hydrogen bond-mediated imprinting of the mono- or dianions of phenyl phosphonic acid (PPA), phenyl sulfonic acid (PSA), and benzoic acid (BA) using N-3,5-bis-(trifluoromethyl)-phenyl-N-4-vinyl-phenyl urea (1) as the functional host monomer. The interaction mode between the functional monomer and the monoanions was elucidated by H-1 NMR titrations and H-1-H-1 NMR NOESY supported by molecular dynamic simulation, which confirmed the presence of high-order complexes. PPA imprinted polymers bound PPA with an equilibrium constant K-eq = 1.8 x 10(5) M-1 in acetonitrile (0.1% 1,2,2,6,6-pentamethylpiperidine) and inorganic HPO42- and SO42- with K-eq = 2.9 X 10(3) M-1 and 4.5 X 10(3) M-1, respectively, in aqueous buffer. Moreover, the chromatographic retentivity of phosphonate versus sulfonate was shown to be completely switched on this polymer when changing from a basic to an acidic modifier. Mechanistic insights into this system were obtained from kinetic investigations and DSC-, MALDI-TOF-MS-, H-1 NMR-studies of linear polymers prepared in the presence of template. The results suggest the formation of template induced 1-1 diad repeats in the polymer main chain shedding unique light on the relative contributions of configurational and conformational imprinting.
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