Methods of screening compounds for the fibril formation of Aβ peptides based on a decreased trimer/monomer ratio of a chaperone protein

摘要

A method involves screening a candidate compound for activity in the treatment of a condition associated with formation of amyloid protein fibrils in a mammal, such as Alzheimer's disease. It is determined whether the trimer/monomer ratio of a chaperone protein is decreased in the presence of the candidate compound. The chaperone protein is or has a high identity to the Brichos domains of Bri2, Bri3 or proSP-C from human. Monomers of the chaperone proteins and/or compounds that promote formation of these monomers are useful for medical treatment of the condition.

主权项

1. A method of screening a candidate compound for activity in activating a chaperon protein that decreases the fibril formation of Aβ-peptide, the method comprising determining whether the trimer/monomer ratio of a chaperone protein decreases in the presence of the candidate compound, wherein a decrease in the trimer/monomer ratio is associated with activity in activating the chaperon protein that decreases the fibril formation, wherein the chaperon protein comprises the amino acid sequence selected from the group consisting of SEQ ID NO:3 and residues 90-243 of integral membrane protein 2B (Bri2) from human (SEQ ID NO: 2), wherein determining whether the trimer/monomer ratio of a chaperone protein is decreased comprises the steps of:
a) adding the candidate compound to an aqueous mixture comprising a known trimer/monomer ratio of the chaperone protein; b) allowing the candidate compound to interact with the chaperone protein in the mixture; c) determining the trimer/monomer ratio of the chaperone protein in the mixture; d) concluding that the candidate compound is d1) active in activating the chaperone protein if the trimer/monomer ratio of the chaperone protein is decreased in the presence of the candidate compound; or d2) not active in activating the chaperone protein if the trimer/monomer ratio of the chaperone protein is not decreased in the presence of the candidate compound.