Amyloid disease prevention by transthyretin native state complexation with carborane derivatives lacking cyclooxygenase inhibition.

Abstract

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.

• Authors: Richard L Julius, M Frederick Hawthorne
• Journal: Drug news & perspectives (Drug News Perspect) Vol. 21 Issue 5 Pg. 258-66 (Jun 2008) ISSN: 0214-0934 [Print] United States
• PMID: 18596990 (Publication Type: Journal Article, Review)
• Copyright: Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.

Chemical References

• Amyloid
• Anti-Inflammatory Agents, Non-Steroidal
• Boranes
• Cyclooxygenase Inhibitors
• Prealbumin
• Thyroxine

Topics

• Amyloid (antagonists & inhibitors)
• Amyloidosis (drug therapy, metabolism)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Binding Sites
• Boranes (adverse effects, metabolism, therapeutic use)
• Cyclooxygenase Inhibitors (pharmacology)
• Drug Design
• Humans
• Prealbumin (chemistry, metabolism)
• Protein Conformation
• Protein Folding
• Structure-Activity Relationship
• Thyroxine (metabolism)