Aromatic sulfonyl fluorides covalently kinetically stabilize transthyretin to prevent amyloidogenesis while affording a fluorescent conjugate

J Am Chem Soc. 2013 Apr 17;135(15):5656-68. doi: 10.1021/ja311729d. Epub 2013 Feb 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / chemistry*
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / pharmacology
  • Fluorine / chemistry*
  • Humans
  • Kinetics
  • Models, Molecular
  • Prealbumin / chemistry*
  • Protein Multimerization / drug effects*
  • Protein Stability / drug effects
  • Protein Structure, Secondary
  • Sulfones / chemistry*
  • Sulfones / pharmacology*

Substances

  • Amyloid
  • Fluorescent Dyes
  • Prealbumin
  • Sulfones
  • Fluorine