Compositions and methods for treatment of protein misfolding and protein aggregation diseases
OwnerJoy Ghosh, John Clarkinventors
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Abstract
Small molecular weight molecules are provided including, but not limited to, peptides, peptide analogs and peptide mimetics that stabilize and prevent the aggregation of abnormally folded and compromised proteins. Methods for treatment of disease are provided utilizing the peptides, peptide analogs or peptide mimetics, or utilizing nucleic acids encoding the peptides.
Claims51
A polypeptide X1-HGKHEERQDE-X2 (SEQ ID NO:85), or a functional variant or mimetic thereof,
- wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2.
A polypeptide X1-HGKH-X2 (SEQ ID NO:86), X1-KHEE-X2 (SEQ ID NO:87), X1-EERQDE-X2 (SEQ ID NO:88), X1-RQDE-X2 (SEQ ID NO:89), X1-EERQ-X2 (SEQ ID NO:90), X1-HGKHEE-X2 (SEQ ID NO:91), X1-KHEERQ-X2 (SEQ ID NO:92), X1-HEER-X2 (SEQ ID NO:93), X1-HGKHEERQ-X2 (SEQ ID NO:94), or X1-KHEERQDE-X2 (SEQ ID NO:95), or a functional variant or mimetic thereof,
- wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2.
A method for treating a protein conformation disease in a mammalian subject comprising administering a polypeptide to the subject in need thereof, wherein the polypeptide is X1-HGKHEERQDE-X2 (SEQ ID NO:85), or a functional variant or mimetic thereof, wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2.
A method for stabilizing a protein comprising contacting the protein with a polypeptide X1-HGKHEERQDE-X2 (SEQ ID NO:85), or a functional variant or mimetic thereof, wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2.
A method for diagnosing a protein conformation disease in a mammalian subject comprising:
- contacting a tissue sample from the mammalian subject with a polypeptide X1-HGKHEERQDE-X2 (SEQ ID NO:85), or a functional variant or mimetic thereof, wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2,
- detecting binding of a misfolded protein, an unfolded protein, or an aggregated protein to the polypeptide, and
- determining a presence or absence of the disease in the mammalian subject.
An in vitro method of screening for a modulator of protein misfolding, protein unfolding, or protein aggregation activity comprising:
- contacting a target protein with a polypeptide X1-HGKHEERQDE-X2 (SEQ ID NO:85), or a functional variant or mimetic thereof, wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2,
- and detecting a decrease in the amount of protein aggregation activity;
- thereby identifying the polypeptide as a modulator of protein misfolding, protein unfolding, or protein aggregation activity.
An in vivo method of screening for a modulator of protein misfolding, protein unfolding, or protein aggregation activity comprising:
- contacting a cell or cell line expressing a target protein with a test compound encoding a polypeptide X1-HGKHEERQDE-X2 (SEQ ID NO:85), or a functional variant or mimetic thereof, wherein each X1 and X2 independently of one another represents any amino acid sequence of n amino acids, n varying from 0 to 50, and n being identical or different in X1 and X2,
- and detecting a decrease in the amount of protein aggregation activity in the cell line, thereby identifying the polypeptide as a modulator of protein misfolding, protein unfolding, or protein aggregation activity.
Dependencies are inferred from the claim text.