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

被引:146
作者
Grimster, Neil P. [1 ]
Connelly, Stephen [2 ]
Baranczak, Aleksandra [1 ]
Dong, Jiajia [1 ]
Krasnova, Larissa B. [1 ]
Sharpless, K. Barry [1 ,4 ]
Powers, Evan T. [1 ]
Wilson, Ian A. [2 ,4 ]
Kelly, Jeffery W. [1 ,3 ,4 ]
机构
[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[3] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
[4] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
基金
美国国家卫生研究院;
关键词
SENILE SYSTEMIC AMYLOIDOSIS; FIBRIL INHIBITORS; IRREVERSIBLE INHIBITORS; SUBSTRUCTURE COMMON; OLIGOMERIC PROTEIN; NATIVE-STATE; POTENT; VARIANT; DISEASE; POLYNEUROPATHY;
D O I
10.1021/ja311729d
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 t(50)s range from 1 to 4 min, similar to 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.
引用
收藏
页码:5656 / 5668
页数:13
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