Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma

Proceedings of the National Academy of Sciences of the United States of America
Hans E PurkeyJeffery W Kelly

Abstract

Transthyretin (TTR) tetramer dissociation and misfolding facilitate assembly into amyloid fibrils that putatively cause senile systemic amyloidosis and familial amyloid polyneuropathy. We have previously discovered more than 50 small molecules that bind to and stabilize tetrameric TTR, inhibiting amyloid fibril formation in vitro. A method is presented here to evaluate the binding selectivity of these inhibitors to TTR in human plasma, a complex biological fluid composed of more than 60 proteins and numerous small molecules. Our immunoprecipitation approach isolates TTR and bound small molecules from a biological fluid such as plasma, and quantifies the amount of small molecules bound to the protein by HPLC analysis. This approach demonstrates that only a small subset of the inhibitors that saturate the TTR binding sites in vitro do so in plasma. These selective inhibitors can now be tested in animal models of TTR amyloid disease to probe the validity of the amyloid hypothesis. This method could be easily extended to evaluate small molecule binding selectivity to any protein in a given biological fluid without the necessity of determining or guessing which other protein components may be competitors. This is a central issue to ...Continue Reading

References

Mar 1, 1976·Journal of Pharmaceutical Sciences·L AngelucciS Favilli
Jan 1, 1992·Annual Review of Biochemistry·J D Sipe
Jan 1, 1991·Advances in Human Genetics·D R Jacobson, J N Buxbaum
Apr 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·P WestermarkG G Cornwell
Jun 1, 1989·The Journal of Clinical Endocrinology and Metabolism·S L MunroJ R Stockigt
Jul 29, 1988·Biochemical and Biophysical Research Communications·G G CornwellP Westermark
Jan 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·D A KirschnerD J Selkoe
Oct 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·A Horovitz, A Levitzki
Jan 1, 1968·Journal of Medicinal Chemistry·P F JubyM Brown
Mar 11, 1983·Journal of Immunological Methods·B J WeiblenC R Valeri
Jan 1, 1995·Human Mutation·M J Saraiva
Nov 1, 1994·Histopathology·S Y Tan, M B Pepys
Jan 1, 1994·Critical Reviews in Clinical Laboratory Sciences·J D Sipe
Jan 1, 1994·Clinical Pharmacokinetics·F HervéJ P Tillement
Jun 7, 1994·Proceedings of the National Academy of Sciences of the United States of America·M R HurleR Wetzel
Feb 1, 1996·Current Opinion in Structural Biology·J W Kelly
Oct 1, 1996·Current Opinion in Neurology·T Coelho
Feb 1, 1996·Journal of Protein Chemistry·W B StineG A Krafft
Feb 23, 1996·Journal of Chromatography. B, Biomedical Applications·J OravcováW Lindner
Dec 24, 1996·Proceedings of the National Academy of Sciences of the United States of America·G J MiroyJ W Kelly
Feb 13, 1997·The New England Journal of Medicine·D R JacobsonJ N Buxbaum
Feb 1, 1997·Chemistry & Biology·J D HarperP T Lansbury
Nov 14, 1997·Journal of Molecular Biology·M SundeC C Blake
Dec 10, 1997·Journal of Chromatography. B, Biomedical Sciences and Applications·D S Hage, S A Tweed
Mar 14, 1998·Proceedings of the National Academy of Sciences of the United States of America·J W Kelly
Aug 26, 1998·Biochemical and Biophysical Research Communications·H TerazakiM Ando
Oct 10, 1998·European Journal of Clinical Investigation·O B SuhrG Holmgren
Oct 24, 1998·Bioorganic & Medicinal Chemistry·P W BauresJ W Kelly
Nov 13, 1998·Proceedings of the National Academy of Sciences of the United States of America·T L BenzingerS C Meredith
Feb 17, 1999·Bioorganic & Medicinal Chemistry Letters·V B OzaJ W Kelly
Mar 31, 2000·Nature Structural Biology·T KlabundeJ C Sacchettini
Jun 8, 2000·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·L H ConnorsC E Costello

❮ Previous
Next ❯

Citations

Jan 19, 2010·Nature Chemical Biology·Sungwook ChoiJeffery W Kelly
Jul 18, 2002·Nature Reviews. Drug Discovery·James C Sacchettini, Jeffery W Kelly
Nov 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Simon E KolstoeMark B Pepys
May 31, 2012·Proceedings of the National Academy of Sciences of the United States of America·Christine E BulawaRichard Labaudinière
May 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Sravan C PenchalaMamoun M Alhamadsheh
May 4, 2007·Annals of Nutrition & Metabolism·Florian J Schweigert
Jan 30, 2003·Clinical Chemistry and Laboratory Medicine : CCLM·Jackie A WilceDavid J Craik
Oct 1, 2005·Proceedings of the National Academy of Sciences of the United States of America·Nora S GreenJeffery W Kelly
Jul 9, 2014·Expert Opinion on Investigational Drugs·Laura Obici, Giampaolo Merlini
Sep 19, 2003·Biomedical Chromatography : BMC·Tibor CserhátiAdam Echardt
Jul 16, 2008·Molecular and Cellular Endocrinology·Isabel MorgadoDeborah M Power
Feb 10, 2007·General and Comparative Endocrinology·I MorgadoD M Power
Sep 5, 2015·Nature Reviews. Drug Discovery·Yvonne S EiseleJeffery W Kelly
May 27, 2010·IUBMB Life·Márcia A LizMónica M Sousa
Aug 15, 2006·Biochemical and Biophysical Research Communications·Natàlia ReixachJoel N Buxbaum
Sep 25, 2015·Open Biology·P Patrizia MangioneGraham W Taylor
Oct 17, 2012·Biochimica Et Biophysica Acta·Nelson FerreiraMaria Rosário Almeida
May 12, 2011·Biochemical and Biophysical Research Communications·Steve BourgaultNatàlia Reixach
May 12, 2016·Journal of Internal Medicine·M AnkarcronaJ W Kelly
Jan 12, 2017·International Journal of Molecular Sciences·Eun Ju LeeInho Choi
Dec 22, 2004·Chemistry & Biology·David L Van Vranken
Feb 3, 2005·Bioorganic & Medicinal Chemistry Letters·Hossein RazaviJeffery W Kelly
Feb 18, 2004·Laboratory Investigation; a Journal of Technical Methods and Pathology·Sean R MillerJeffery W Kelly
Jan 20, 2006·Muscle & Nerve·Merrill D BensonKyle W Sloop
Nov 17, 2006·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Yoshiki SekijimaJeffery W Kelly
Jun 18, 2004·The Biochemical Journal·Melissa H Y ChangPeter J Meikle
Apr 9, 2020·Cardiology and Therapy·Adam S Hafeez, Anthony A Bavry
Feb 19, 2017·Clinical Science·Natalie J GalantAvijit Chakrabartty

❮ Previous
Next ❯

Related Concepts

Related Feeds

Amyloidogenesis-associated Polyneuropathy

Amyloid deposits around nerves can damage and disrupt smooth information processing between the brain and organs. Here is the latest research on amyloidosis-associated polyneuropathies.