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Wu, Xiongyu
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Publications (5 of 5) Show all publications
Silverå Ejneby, M., Wu, X., Ottosson, N., Münger, E. P., Lundström, I., Konradsson, P. & Elinder, F. (2018). Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid. The Journal of General Physiology, 150(5), 731-750
Open this publication in new window or tab >>Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
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2018 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 5, p. 731-750Article in journal (Refereed) Published
Abstract [en]

Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel’s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel’s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.

Place, publisher, year, edition, pages
New York, United States: Rockefeller Institute for Medical Research, 2018
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-147837 (URN)10.1085/jgp.201711965 (DOI)000434417800008 ()2-s2.0-85046705149 (Scopus ID)
Note

Funding agencies: Swedish Research Council [2016-02615]; Swedish Heart-Lung Foundation [20150672]; Swedish Brain Foundation [2016-0326]

Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2018-06-28Bibliographically approved
Zhang, J., Wang, J., Sandberg, A., Wu, X., Nyström, S., LeVine, H. I., . . . Lindgren, M. (2018). Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.. ChemPhysChem, 19(22), 3001-3009
Open this publication in new window or tab >>Intramolecular Proton and Charge Transfer of Pyrene-based trans-Stilbene Salicylic Acids Applied to Detection of Aggregated Proteins.
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2018 (English)In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 19, no 22, p. 3001-3009Article in journal (Refereed) Published
Abstract [en]

Two analogues to the fluorescent amyloid probe 2,5-bis(4'-hydroxy-3'-carboxy-styryl)benzene (X-34) were synthesized based on the trans-stilbene pyrene scaffold (Py1SA and Py2SA). The compounds show strikingly different emission spectra when bound to preformed Aβ1-42 fibrils. This remarkable emission difference is retained when bound to amyloid fibrils of four distinct proteins, suggesting a common binding configuration for each molecule. Density functional theory calculations show that Py1SA is twisted, while Py2SA is more planar. Still, an analysis of the highest occupied molecular orbitals (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) of the two compounds indicates that the degree of electronic coupling between the pyrene and salicylic acid (SA) moieties is larger in Py1SA than in Py2SA. Excited state intramolecular proton transfer (ESIPT) coupled-charge transfer (ICT) was observed for the anionic form in polar solvents. We conclude that ICT properties of trans-stilbene derivatives can be utilized for amyloid probe design with large changes in emission spectra and decay times from analogous chemical structures depending on the detailed physical nature of the binding site.less thanbr /greater than (© 2018 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.)

Place, publisher, year, edition, pages
Weinheim, Germany: Wiley-VCH Verlag, 2018
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:liu:diva-152767 (URN)10.1002/cphc.201800823 (DOI)000450672100006 ()30183138 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2018-12-10
Zhang, J., Sandberg, A., Wu, X., Nyström, S., Lindgren, M., Konradsson, P. & Hammarström, P. (2017). trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils. ACS Omega, 2(8), 4693-4704
Open this publication in new window or tab >>trans-Stilbenoids with Extended Fluorescence Lifetimes for the Characterization of Amyloid Fibrils
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2017 (English)In: ACS Omega, ISSN 2470-1343, Vol. 2, no 8, p. 4693-4704Article in journal (Refereed) Published
Abstract [en]

It was previously reported that two naphthyl-based trans-stilbene probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (1) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (3), can bind to both native transthyretin (TTR) and misfolded protofibrillar TTR at physiological concentrations, displaying distinct emission maxima bound to the different conformational states (>100 nm difference). To further explore this amyloid probe scaffold to obtain extended fluorescence lifetimes, two new analogues with expanded aromatic ring systems (anthracene and pyrene), (E)-4-(2-(anthracen-2-yl)vinyl)benzene-1,2-diol (4) and (E)-4-(2-(pyren-2-yl)vinyl)benzene-1,2-diol (5), were synthesized employing the palladium-catalyzed Mizoroki–Heck reaction. (E)-4-Styrylbenzene-1,2-diol (2), 3, 4, and 5 were investigated with respect to their photophysical properties in methanol and when bound to insulin, lysozyme, and Aβ1-42 fibrils, including time-resolved fluorescence measurements. In conclusion, 4 and 5 can bind to both native and fibrillar TTR, becoming highly fluorescent. Compounds 2–5 bind specifically to insulin, lysozyme, and Aβ1-42 fibrils with an apparent fluorescence intensity increase and moderate binding affinities. The average fluorescence lifetimes of the probes bound to Aβ1-42 fibrils are 1.3 ns (2), 1.5 ns (3), 5.7 ns (4), and 29.8 ns (5). In summary, the variable aromatic moieties of the para-positioned trans-stilbenoid vinyl-benzene-1,2-diol with benzene, naphthalene, anthracene, and pyrene showed that the extended conjugated systems retained the amyloid targeting properties of the probes. Furthermore, both the anthracene and pyrene moieties extensively enhanced the fluorescence intensity and prolonged lifetimes. These attractive probe properties should improve amyloid detection and characterization by fluorescence-based techniques.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
Keywords
Fluorescence; Glycoproteins; Molecular association; Molecular recognition; Optical materials; Quantum transition; Spectra
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-151658 (URN)10.1021/acsomega.7b00535 (DOI)000409924000069 ()
Available from: 2018-09-28 Created: 2018-09-28 Last updated: 2018-11-20Bibliographically approved
Campos Melo, R. I., Wu, X., Elgland, M., Konradsson, P. & Hammarström, P. (2016). Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin. ACS Chemical Neuroscience, 7(7), 924-940
Open this publication in new window or tab >>Novel Trans-Stilbene-based Fluorophores as Probes for Spectral Discrimination of Native and Protofibrillar Transthyretin
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2016 (English)In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 7, p. 924-940Article in journal (Refereed) Published
Abstract [en]

Accumulation of misfolded transthyretin (TTR) as amyloid fibrils causes various human disorders. Native transthyretin is a neurotrophic protein and is a putative extracellular molecular chaperone. Several fluorophores have been shown in vitro to bind selectively to native TTR. Other compounds, such as thioflavin T, bind TTR amyloid fibrils. The probe 1-anilinonaphthalene-8-sulfonate (ANS) binds to both native and fibrillar TTR, becoming highly fluorescent, but with indistinguishable emission spectra for native and fibrillar TTR. Herein we report our efforts to develop a fluorescent small molecule capable of binding both native and misfolded protofibrillar TTR, providing distinguishable emission spectra. We used microwave synthesis for efficient production of a small library of trans-stilbenes and fluorescence spectral screening of their binding properties. We synthesized and tested 22 trans-stilbenes displaying a variety of functional groups. We successfully developed two naphthyl-based trans-stilbenes probes that detect both TTR states at physiological concentrations. The compounds bound with nanomolar to micromolar affinities and displayed distinct emission maxima upon binding native or misfolded protofibrillar TTR (>100 nm difference). The probes were mainly responsive to environment polarity providing evidence for the divergent hydrophobic structure of the binding sites of these protein conformational states. Furthermore, we were able to successfully use one of these probes to quantify the relative amounts of native and protofibrillar TTR in a dynamic equilibrium. In conclusion, we identified two trans-stilbene-based fluorescent probes, (E)-4-(2-(naphthalen-1-yl)vinyl)benzene-1,2-diol (11) and (E)-4-(2-(naphthalen-2-yl)vinyl)benzene-1,2-diol (14), that bind native and protofibrillar TTR, providing a wide difference in emission maxima allowing conformational discrimination by fluorescence spectroscopy. We expect these novel molecules to serve as important chemical biology research tools in studies of TTR folding and misfolding.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
Keywords
transthyretin, amyloid, stilbene, fluorescence, probe, spectrum
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122842 (URN)10.1021/acschemneuro.6b00062 (DOI)000380297500009 ()27144293 (PubMedID)
Note

At the time for thesis presentation publication was in status: Manuscript

Funding agencies:The work was supported by Goran Gustafsson's Foundation (PH), The Swedish Research Council (PH), The Linkoping center for systemic neuroscience, LiU-Neuro, (XW), and Sven and Lilly Lawski's foundation (ME).

Available from: 2015-11-26 Created: 2015-11-26 Last updated: 2018-04-25Bibliographically approved
Ottosson, N., Wu, X., Nolting, A., Karlsson, U., Lund, P.-E., Ruda, K., . . . Elinder, F. (2015). Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability. Scientific Reports, 5(13278)
Open this publication in new window or tab >>Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 13278Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121307 (URN)10.1038/srep13278 (DOI)000359905300001 ()26299574 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; ALF; County Council of Ostergotland

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-01-25Bibliographically approved
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