Document Detail


Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate.
MedLine Citation:
PMID:  23350654     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Molecules that bind selectively to a given protein and then undergo a rapid chemoselective reaction to form a covalent conjugate have utility in drug development. Herein a library of 1,3,4-oxadiazoles substituted at the 2 position with an aryl sulfonyl fluoride and at the 5 position with a substituted aryl known to have high affinity for the inner thyroxine binding subsite of transthyretin (TTR) was conceived of by structure-based design principles and was chemically synthesized. When bound in the thyroxine binding site, most of the aryl sulfonyl fluorides react rapidly and chemoselectively with the pKa-perturbed K15 residue, kinetically stabilizing TTR and thus preventing amyloid fibril formation, known to cause polyneuropathy. Conjugation t50s range from 1 to 4 min, ~1400 times faster than the hydrolysis reaction outside the thyroxine binding site. X-ray crystallography confirms the anticipated binding orientation and sheds light on the sulfonyl fluoride activation leading to the sulfonamide linkage to TTR. A few of the aryl sulfonyl fluorides efficiently form conjugates with TTR in plasma. Eleven of the TTR covalent kinetic stabilizers synthesized exhibit fluorescence upon conjugation and therefore could have imaging applications as a consequence of the environment sensitive fluorescence of the chromophore.
Authors:
Neil P Grimster; Stephen Connelly; Aleksandra Baranczak; Jiajia Dong; Larissa B Krasnova; K Barry Sharpless; Evan T Powers; Ian A Wilson; Jeffery W Kelly
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-14
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  135     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-17     Completed Date:  2013-10-21     Revised Date:  2014-04-18    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5656-68     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amyloid / chemistry*
Fluorescent Dyes / chemistry,  pharmacology
Fluorine / chemistry*
Humans
Kinetics
Models, Molecular
Prealbumin / chemistry*
Protein Multimerization / drug effects*
Protein Stability / drug effects
Protein Structure, Secondary
Sulfones / chemistry*,  pharmacology*
Grant Support
ID/Acronym/Agency:
AI42266/AI/NIAID NIH HHS; CA58896/CA/NCI NIH HHS; DK046335/DK/NIDDK NIH HHS; R01 AI042266/AI/NIAID NIH HHS; R01 CA058896/CA/NCI NIH HHS; R37 AI042266/AI/NIAID NIH HHS; R37 DK046335/DK/NIDDK NIH HHS; U01 NS058046/NS/NINDS NIH HHS; U01NS058046/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid; 0/Fluorescent Dyes; 0/Prealbumin; 0/Sulfones; 284SYP0193/Fluorine
Comments/Corrections

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