Methods for treating transthyretin amyloid diseases

Abstract

Kinetic stabilization of the native state of transthyretin is an effective mechanism for preventing protein misfolding. Because transthyretin misfolding plays an important role in transthyretin amyloid diseases, inhibiting such misfolding can be used as an effective treatment or prophylaxis for such diseases. Treatment methods are disclosed.

1 - 24 . (canceled) 
     
     
         25 . A method of screening for a compound that prevents or reduces dissociation of a transthyretin tetramer, the method comprising:
 contacting a transthyretin tatramer with a candiate compound; and determining whether the candidate compound increases the activation energy associated with the dissociation of the transthyretin tetramer, thereby preventing or reducing dissociation of the transthyretin tetramer.   
     
     
         26 . The method of  claim 25 , comprising determining whether the compound prevents dissociation of the transthyretin tetramer by destabilizing the dissociation transition state of the transthyretin tetramer. 
     
     
         27 . The method of  claim 25 , comprising determining whether the compound prevents dissociation of the transthyretin tetramer by stabilization of the transthyretin tetramer. 
     
     
         28 . The method of  claim 25 , further comprising measuring the ability of the candidate compound to inhibit fibril formation. 
     
     
         29 . The method of  claim 25 , wherein the transthyretin tetramer comprises wild type transthyretin. 
     
     
         30 . The method of  claim 25 , wherein the transthyretin tetramer comprises a naturally occurring mutant transthyretin. 
     
     
         31 . The method of  claim 30 , wherein the transthyretin tetramer comprises a naturally occurring mutant transthyretin causally associated with the incidence of familial amyloid polyneuropathy. 
     
     
         32 . The method of  claim 30 , wherein the transthyretin tetramer comprises a naturally occurring mutant transthyretin causally associated with the incidence of familial amyloid cardiomyopathy. 
     
     
         33 . The method of  claim 25 , wherein the transthyretin tetramer comprises the mutant transthyretin V122I. 
     
     
         34 . The method of  claim 25 , wherein the transthyretin tetramer comprises the mutant transthyretin V30M. 
     
     
         35 . The method of  claim 25 , wherein the transthyretin tetramer comprises the mutant transthyretin L55P. 
     
     
         36 . The method of  claim 25 , wherein the candidate compound is a small molecule compound. 
     
     
         37 . The method of  claim 25 , wherein the candidate compound is selected from a diflunisal analog, a benzoxazole, and a polychlorinated biphenyl. 
     
     
         38 . The method of  claim 37 , wherein the diflunisal analog has reduced or absent NSAID activity as compared to diflunisal. 
     
     
         39 . The method of  claim 37 , wherein the diflunisal analog has reduced or absent cyclooxygenase inhibitor activity as compared to diflunisal. 
     
     
         40 . The method of  claim 37 , further comprising determining whether the diflunisal analog exhibits NSAID activity. 
     
     
         41 . The method of  claim 37 , further comprising determining whether the diflunisal analog exhibits cyclooxygenase inhibitor activity. 
     
     
         42 . The method of  claim 37 , wherein the polychlorinated biphenyl is a hydroxylated polychlorinated biphenyl.