Discordant helix stabilization for prevention of amyloid formation

• US 9,580,460 B2
• Filed: 11/08/2013
• Issued: 02/28/2017
• Est. Priority Date: 11/20/2000
• Status: Expired due to Fees

• Current Assignee: Alphabeta AB
• Original Assignee: Alphabeta AB
• Inventors: Johansson, Jan
• Primary Examiner(s): STANFIELD, CHERIE MICHELLE
• Application Number:
  US14/074,895
• Publication Number:
  US 20140187747A1
• Time in Patent Office: 1,208 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 1/1136 by reversible modification of the secondary, tertiary or quarternary structure, e.g. using denaturating or stabilising agents
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 2800/2828 Prion diseases
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

The invention is based on the discovery that the presence of a discordant helix in a protein or peptide is predictive of that protein or peptide'"'"'s ability to form amyloid. The invention includes methods for detecting discordant helices and methods of screening for compounds that stabilize the α-helix of a discordant helix-containing polypeptide. Compounds discovered using these methods are useful for treating or preventing disorders in which amyloid is produced. Such disorders include Alzheimer'"'"'s disease and prion-associated disorders.

Claims

1. A method of decreasing the rate of formation of β

-strand structures between at least two discordant helix-containing polypeptides, the method comprising contacting the discordant helix-containing polypeptides with a dipolar tripeptide that stabilizes an α

-helical form of at least one discordant helix, wherein the dipolar tripeptide stabilizes an α

-helical form of at least one discordant helix, thereby decreasing the rate of formation of β

-strand structures between the discordant helix-containing polypeptides, and wherein the discordant helix-containing polypeptides are each independently Aβ

peptides.

2. The method of claim 1, wherein said polypeptides have sequences that, in the absence of stabilization, are predicted to be able to form α

-helices and are also predicted to be able to form β

-strands.

3. The method of claim 1, wherein the dipolar tripeptide is selected from KAD, KFD, DAK, DFK, RAD, RFD, DAR, DFR, KAE, KFE, EAK, EFK, RAE, RFE, EAR, EFR, or any of said peptides, but with the middle residue replaced with another uncharged residue.

4. The method of claim 1, wherein the dipolar tripeptide has protected termini.

5. The method of claim 1, wherein at least one discordant helix comprises Aβ

(1-40).

6. The method of claim 1, wherein at least one discordant helix comprises residues 14-23 of the Aβ

peptide.

7. The method of claim 1, wherein at least one discordant helix comprises residues 16-23 of the Aβ

peptide.