Trehalose Conjugates of Silybin as Prodrugs for Targeting Toxic Aβ Aggregates.

ACS Chemical Neuroscience
Sara García-ViñualesDanilo Milardi

Abstract

Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (Silybum marianum), has been shown to significantly inhibit Aβ aggregation in vitro and to exert neuroprotective properties in vivo. However, further explorations of silybin B's clinical potential are currently limited by three main factors: (a) poor solubility, (b) instability in blood serum, and (c) only partial knowledge of silybin's mechanism of action. Here, we address these three limitations. We demonstrate that conjugation of a trehalose moiety to silybin significantly increases both water solubility and stability in blood serum without significantly compromising its antiaggregation properties. Furthermore, using a combination of biophysical techniques with different spatial resolution, that is, TEM, ThT fluorescence, CD, and NMR spectroscopy, we profile the interactions of the trehalose conjugate with both Aβ monomers and oligomers and evidence that silybin may shield the "toxic" surfaces formed by the N-terminal and central hydrophobic regions of Aβ. Finally, comparative analysis with silybin A, a less active diastereoisomer of silybin B, revealed h...Continue Reading

References

Jan 1, 1995·Journal of Drug Targeting·M S Wadhwa, K G Rice
Oct 1, 1994·Reviews in the Neurosciences·F CoriaC Bayón
Jul 1, 1993·European Journal of Drug Metabolism and Pharmacokinetics·P MorazzoniG Pifferi
May 30, 1998·Proceedings of the National Academy of Sciences of the United States of America·M P LambertW L Klein
Jun 1, 1999·Journal of Ethnopharmacology·L La GrangeE Reyes
Nov 7, 1999·The Journal of Biological Chemistry·D S YangP E Fraser
Jun 12, 2002·The Journal of Biological Chemistry·Karie N DahlgrenMary Jo LaDu
Oct 26, 2002·Science·Dennis J Selkoe
Mar 17, 2004·Journal of Pharmaceutical and Biomedical Analysis·Y H HanM Ji
Sep 9, 2006·Brain Research Reviews·Petrea FridNatalija Popovic
Feb 3, 2007·Current Topics in Medicinal Chemistry·L D Estrada, C Soto
Mar 13, 2008·Forschende Komplementärmedizin = Research in Complementary Medicine·Reinhard SallerRémy Meier
Aug 28, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Maria Laura GiuffridaAgata Copani
Oct 21, 2009·Journal of Clinical Pharmacology·Roy L HawkeUNKNOWN SyNCH Trial Group
Dec 17, 2009·Molecular Nutrition & Food Research·Charles-Henry CottartJean-Louis Beaudeux
Mar 1, 2012·Biochemical and Biophysical Research Communications·Biao ChengKun Huang
Jul 31, 2012·Advances in Pharmacology·Keran MaJoAnne McLaurin
Feb 22, 2013·Proceedings of the National Academy of Sciences of the United States of America·Suk-Joon HyungMi Hee Lim
Aug 7, 2013·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Sílvia CufíJavier A Menendez
Sep 28, 2013·Journal of Alzheimer's Disease : JAD·Julijana MilojevicGiuseppe Melacini
Nov 19, 2013·The Journal of Pharmacy and Pharmacology·Jing DuZhao Wang
Oct 5, 2014·Biochimica Et Biophysica Acta·Stéphane BastianettoRémi Quirion
Oct 14, 2014·Frontiers in Aging Neuroscience·Shraddha D RegeJeganathan Ramesh Babu
Feb 2, 2015·European Journal of Medicinal Chemistry·Fabio LolicatoCarmelo La Rosa
May 29, 2015·Journal of Peptide Science : an Official Publication of the European Peptide Society·Tian QiuYan-Mei Li
Jun 1, 2017·ACS Chemical Neuroscience·Michele F M SciaccaDanilo Milardi
Aug 12, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Valeria RomanucciGiovanni Di Fabio
Aug 26, 2017·Journal of the American Chemical Society·Rashik AhmedGiuseppe Melacini
Nov 11, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Michal Bijak
Apr 17, 2018·Chemical Communications : Chem Comm·Rashik Ahmed, Giuseppe Melacini
Jul 31, 2019·Chemical Science·Rashik AhmedGiuseppe Melacini
Dec 13, 2019·Nature Reviews. Neurology·Steven M GreenbergSusanne J van Veluw
Jul 25, 2020·Biophysical Chemistry·Valeria RomanucciGiovanni Di Fabio

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Mar 7, 2021·Chemistry and Physics of Lipids·Sara García-ViñualesDanilo Milardi
Aug 8, 2021·International Journal of Molecular Sciences·Vladimír Křen

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