A strategy for designing inhibitors of beta-amyloid toxicity.

The Journal of Biological Chemistry
J GhantaRegina M Murphy

Abstract

beta-Amyloid peptide is the major protein component of Alzheimer's plaques. When aggregated into amyloid fibrils, the peptide is toxic to neuronal cells. Here, an approach to the design of inhibitors of beta-amyloid toxicity is described; in this strategy, a recognition element, which interacts specifically with beta-amyloid, is combined with a disrupting element, which alters beta-amyloid aggregation pathways. The synthesis, biophysical characterization, and biological activity of such an inhibitor is reported. This prototype inhibitor is composed of residues 15-25 of beta-amyloid peptide, designed to function as the recognition element, linked to an oligolysine disrupting element. The inhibitor does not alter the apparent secondary structure of beta-amyloid nor prevent its aggregation; rather, it causes changes in aggregation kinetics and higher order structural characteristics of the aggregate. Evidence for these effects includes changes in fibril morphology and a reduction in thioflavin T fluorescence. In addition to its influence on the physical properties of beta-amyloid aggregates, the inhibitor completely blocks beta-amyloid toxicity to PC-12 cells. Together, these data suggest that this general strategy for design of b...Continue Reading

References

Jan 1, 1992·Alzheimer Disease and Associated Disorders·C L Joachim, D J Selkoe
Nov 1, 1991·Biophysical Journal·P E FraserD A Kirschner
Dec 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·C W WongG G Glenner
May 16, 1984·Biochemical and Biophysical Research Communications·G G Glenner, C W Wong
Mar 21, 1994·FEBS Letters·P CamilleriD R Howlett
Feb 15, 1994·Proceedings of the National Academy of Sciences of the United States of America·M S ShearmanL L Iversen
Aug 1, 1995·Biophysical Journal·C L Shen, R M Murphy
Feb 6, 1996·Proceedings of the National Academy of Sciences of the United States of America·A LomakinD B Teplow
Apr 12, 1996·The Journal of Biological Chemistry·L O TjernbergC Nordstedt
Feb 23, 1996·The Journal of Biological Chemistry·S J WoodR Wetzel
Mar 5, 1996·Proceedings of the National Academy of Sciences of the United States of America·S R HughesS R Sahasrabudhe

❮ Previous
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Citations

Nov 24, 1999·Biochemical and Biophysical Research Communications·Z SzabóB Penke
May 15, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jan Bieschke
Jul 11, 2006·Biochemical and Biophysical Research Communications·Sungmun LeeTheresa Good
Jun 28, 2003·Biophysical Journal·S Y FungP Chen
Jan 6, 2000·Progress in Neuro-psychopharmacology & Biological Psychiatry·T HarkanyC Nyakas
Jan 11, 2001·Biophysical Chemistry·J Masel, V A Jansen
Sep 2, 2003·Current Opinion in Structural Biology·Jody M MasonAndrew J Doig
Aug 1, 1997·Current Opinion in Chemical Biology·P T Lansbury
Nov 20, 2012·Proceedings of the National Academy of Sciences of the United States of America·Ali Reza A LadiwalaPeter M Tessier
Jun 25, 2009·Protein Engineering, Design & Selection : PEDS·Lin LiuRegina M Murphy
May 28, 2013·Protein Engineering, Design & Selection : PEDS·Nicola AcerraJody M Mason
Feb 25, 2014·Langmuir : the ACS Journal of Surfaces and Colloids·Akash Saini, Virander S Chauhan
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·T Kowalewski, D M Holtzman
Jan 5, 2011·International Journal of Alzheimer's Disease·Joseph J BraymerMi Hee Lim
Nov 22, 2011·Nature Chemical Biology·Jan BieschkeErich E Wanker
Jan 1, 2009·Expert Opinion on Drug Discovery·Claudio Soto, Zane Martin
Oct 18, 2013·The Protein Journal·Previn NaickerYasien Sayed
Jan 17, 2002·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·M A FindeisS M Molineaux
Jul 16, 2002·Annual Review of Biomedical Engineering·Regina M Murphy
Jun 28, 2016·ACS Chemical Neuroscience·Xiaomeng LuRegina M Murphy
Sep 12, 2009·Experimental Neurology·Kevin A DasilvaJoanne McLaurin
Aug 21, 2007·Biophysical Journal·William F WeissChristopher J Roberts
Jan 31, 2015·Scientific Reports·K RajasekharT Govindaraju
Feb 19, 2005·Chembiochem : a European Journal of Chemical Biology·Carsten SchmuckMartin Heil
May 13, 2008·Biochemical and Biophysical Research Communications·Katsumi MatsuzakiYoshiaki Kiso
Apr 23, 2004·European Journal of Mass Spectrometry·Aiqun Li, Catherine Fenselau

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