Neurodegenerative protein aggregation inhibition methods and compounds
View Patent ↗Methods and compositions are provided for reducing aggregation of neurodegenerative proteins associated with neurotoxicity or other proteins. The compounds comprise a first domain or targeting element for binding to the target proteins linked to a second domain or recruiting element that binds to an aggregation inhibiting protein, e.g. a prolyl isomerase. By associating the aggregating forming proteins or neuronal cells under conditions where aggregating proteins are produced with the compound and the aggregation inhibiting protein, aggregation is reduced. The subject agents can be used in assays, investigating the etiology of the neuronal diseases and for prophylaxis and therapy.
1. A method for diminishing the presence of a protein aggregate in an in vitro environment that includes said protein aggregate and an aggregation diminishing protein, said method comprising:
a. introducing into said environment a compound having the structure:
R1—L-R2
wherein R 1 is a first domain which binds to said protein aggregate and wherein R 1 is Congo red; L is a single bond or a linking group of about 1 to 12 atoms in length; R 2 is a second domain which binds to said aggregation diminishing protein and wherein R 2 is selected from the group consisting of SLF, FK506, rapamycin, and ascomycin; and wherein said aggregation diminishing protein is an enzyme or heat shock protein; and
b. incubating said compound in said environment for a period of time and temperature sufficient to diminish therein the presence of the protein aggregate.
2. The method according to claim 1 , wherein said aggregation diminishing protein sterically interferes with the formation of said protein aggregate.
3. The method according to claim 1 , wherein said protein aggregate comprises at least two monomers and said aggregation diminishing protein enzymatically modifies said monomers to inhibit aggregation therebetween.
4. The method of claim 1 , wherein the protein aggregate is a neurodegenerative protein.
5. The method according to claim 4 , wherein said aggregation diminishing protein is a prolyl isomerase.
6. The method according to claim 5 , wherein said prolyl isomerase is selected from the group consisting of FKBP, cyclophilin, Pin 1, and hParv14.
7. The method according to claim 4 , wherein said aggregation diminishing protein is a heat shock protein.
8. The method according to claim 1 , wherein said protein aggregate is amyloid beta.
9. The method according to claim 1 , wherein L is 4 to 8 atoms in length and further comprises one or more functional groups, each functional group independently selected from the group consisting of an amide, an ether, an aryl, an alkyl, an alkene, an amino acid, and a hydroxy acid.
10. The method according to claim 1 , wherein R 2 is SLF or FK506.