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1. WO2004056315 - COMPOSITIONS ET METHODES PERMETTANT DE STABILISER LA TRANSTHYRETINE ET D'INHIBER UN MAUVAIS REPLIEMENT DE LA TRANSTHYRETINE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

1. A method of screening for a compound that prevents or reduces dissociation of a transthyretin tetramer, the method comprising:
contacting a transthyretin tetramer with a candidate compound; and
determining whether the candidate compound increases the activation energy associated with dissociation ofthe transthyretin tetramer, thereby preventing or reducing dissociation ofthe transthyretin tetramer.

2. The method of claim 1, comprising determining whether the compound prevents dissociation ofthe transthyretin tetramer by destabilizing the dissociation transition state of the transthyretin tetramer.

3. The method of claim 1, comprising determining whether the compound prevents dissociation ofthe transthyretin tetramer by stabilization ofthe transthyretin tetramer.

4. The method of claim 1, further comprising measuring the ability ofthe candidate compound to inhibit fibril formation

5. The method of claim 1, wherein the transthyretin tetramer comprises wild type transthyretin.

6. The method of claim 1, wherein the transthyretin tetramer comprises a naturally occurring mutant transthyretin.

7. The method of claim 1, wherein the transthyretin tetramer comprises a naturally occurring mutant transthyretin causally associated with the incidence of familial amyloid polyneuropathy.

8. The method of claim 1, wherein the transthyretin tetramer comprises a naturally occurring mutant transthyretin causally associated with the incidence of familial amyloid cardiomyopathy.

9. The method of claim 1, wherein the transthyretin tetramer comprises the mutant transthyretin VI 221.

10. The method of claim 1, wherein the transthyretin tetramer comprises the mutant transthyretin V30M.

11. The method of claim 1 , wherein the transthyretin tetramer comprises the mutant transthyretin L55P.

12. The method of claim 1, wherein the candidate compound is a small molecule.

13. The method of claim 1, wherein the candidate compound is a diflunisal analog.

14. The method of claim 13, wherein the diflunisal analog has reduced or absent NSAID activity as compared to diflunisal.

15. The method of claim 13, wherein the diflunisal analog has reduced or absent cyclooxygenase inhibitor activity as compared to diflunisal.

16. The method of claim 1, further comprising determining whether the diflunisal analog exhibits NSAID activity.

17. The method of claim 1, further comprising determining whether the diflunisal analog exhibits cyclooxygenase inhibitor activity.

18. The method of claim 1, wherein the candidate compound is a polychlorinated biphenyl.

19. The method of claim 18, wherein the polychlorinated biphenyl is a hydroxylated polychlorinated biphenyl.

20. A method of treating a fransthyretin amyloid disease, the method comprising administering to a subject diagnosed as having a transthyretin amyloid disease a
therapeutically effective amount of a diflunisal analog that prevents dissociation of a transthyretin tetramer.

21. The method of claim 20, wherein the diflunisal analog prevents dissociation of the fransthyretin tetramer by kinetic stabilization ofthe native state ofthe transthyretin tetramer.

22. The method of claim 20, wherein the transthyretin amyloid disease is familial amyloid polyneuropathy.

23. The method of claim 20, wherein the transthyretin amyloid disease is familial amyloid cardiomyopathy.

24. The method of claim 20, wherein the transthyretin amyloid disease is senile systemic amyloidosis.

25. The method of claim 20, wherein the diflunisal analog has reduced or absent NSAID activity as compared to diflunisal.

26. The method of claim 20, wherein the diflunisal analog has reduced or absent cyclooxygenase inhibitor activity as compared to diflunisal.

27. A method of treating a transthyretin amyloid disease, the method comprising administering to a subject diagnosed as having a transthyretin amyloid disease a
therapeutically effective amount of a polychlorinated biphenyl that prevents dissociation of a transthyretin tetramer. .

28. The method of claim 27, wherein the polychlorinated biphenyl prevents dissociation ofthe fransthyretin tetramer by kinetic stabilization ofthe native state ofthe transthyretin tetramer.

29. The method of claim 27, wherein the polychlorinated biphenyl is a hydroxylated polychlorinated biphenyl.

30. The method of claim 27, wherein the transthyretin amyloid disease is familial amyloid polyneuropathy.

31. The method of claim 27, wherein the transthyretin amyloid disease is familial amyloid cardiomyopathy.

32. The method of claim 27, wherein the transthyretin amyloid disease is senile systemic amyloidosis. .