Aromatic Sulfonyl Fluorides Covalently Kinetically Stabilize Transthyretin to Prevent Amyloidogenesis while Affording a Fluorescent Conjugate

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• 作者：Neil P. Grimster ; Stephen Connelly ; Aleksandra Baranczak ; Jiajia Dong ; Larissa B. Krasnova ; K. Barry Sharpless ; Evan T. Powers ; Ian A. Wilson ; Jeffery W. Kelly
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：April 17, 2013
• 年：2013
• 卷：135
• 期：15
• 页码：5656-5668
• 全文大小：675K
• 年卷期：v.135,no.15(April 17, 2013)
• ISSN：1520-5126

文摘

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 pK_a-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.