Amyloid disease prevention by transthyretin native state complexation with carborane derivatives lacking cyclooxygenase inhibition.
Misfolding and subsequent aggregation of any of a number of proteins leads to the accumulation of amyloid fibrils, which have been associated with a variety of diseases. One such amyloidogenic protein is transthyretin (TTR), a 55-kDa homotetrameric protein found in the blood plasma and cerebrospinal fluid where it binds and transports thyroxine. In humans, the T119M-TTR variant has been shown to be protective against familial amyloid polyneuropathy, a TTR amyloid disease, through kinetic stabilization of the unliganded tetrameric structure. Studies have indicated that a diverse range of small molecules may also bind TTR in the thyroxine-binding pocket and subsequently kinetically stabilize the protein's native conformation in vitro, preventing the misfolding that has been implicated in the progression of several diseases. However, cyclooxygenase inhibition is a common unwanted side effect among such small-molecule kinetic stabilizers. The recent development of transthyretin stabilizers not subject to cyclooxygenase inhibition may prove attractive for the long-term treatment of TTR misfolding diseases in humans. Such compounds are attained by incorporating aromatic carborane icosahedra at strategic points in their structures.
Julius
Richard L
RL
University of California, Los Angeles, California, USA.
Hawthorne
M Frederick
MF
D000682:Amyloid / Q000037:antagonists & inhibitors*; D000686:Amyloidosis / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D001880:Boranes / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013974:Thyroxine / Q000378:metabolism
D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001880:Boranes; D016861:Cyclooxygenase Inhibitors; D011228:Prealbumin; D013974:Thyroxine