Design of mechanism-based inhibitors of transthyretin amyloidosis: studies with biphenyl ethers and new structural templates.
Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (>90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.
Gupta
Sarika
S
Molecular Biophysics Unit, Indian Institute of Sciences, Bangalore 560012, India.
Chhibber
Manmohan
M
Sinha
Sharmistha
S
Surolia
Avadhesha
A
D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D052160:Benzothiazoles; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000737:chemistry; D015195:Drug Design; D005453:Fluorescence; D005976:Glutaral / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D010647:Phenyl Ethers / Q000737:chemistry* / Q000494:pharmacology; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011489:Protein Denaturation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology; D014364:Tryptophan / Q000737:chemistry
C525460:2,3,6-trichloro-N-(4H-(1,2,4)triazol-3-yl)benzamide; C525459:2-(5-mercapto-(1,3,4)oxadiazol-2-yl)phenol; D001549:Benzamides; D052160:Benzothiazoles; D003432:Cross-Linking Reagents; D010069:Oxadiazoles; D010647:Phenyl Ethers; D011228:Prealbumin; D013844:Thiazoles; D014230:Triazoles; C009462:thioflavin T; D014364:Tryptophan; D005976:Glutaral