Peptide inhibitors of BACE1

Patent metadata

Field	Value
Publication number	US-9624269-B2
Application number	US-201514948173-A
Country	US
Kind code	B2
Filing date	Nov 20, 2015
Priority date	Oct 14, 2011
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

The invention provides peptide inhibitors of BACE1 that bind to the active site in a noncanonical fashion, and methods of use thereof.

First claim

What is claimed is:

1. An isolated polynucleotide encoding a polypeptide comprising the amino acid sequence X1-S-X2-Y-C-R-L-X3-X4-X5-X6-C-(X7) n (SEQ ID NO: 6), wherein X1 is glutamic acid or aspartic acid: wherein X2 is methionine, leucine, isoleucine or valine; wherein X3 is leucine or methionine: wherein X4 is glycine, serine or alanine; wherein X5 is leucine, isoleucine or valine; wherein X6 is glycine or alanine; wherein X7 is glycine, aspartic acid or glutamic acid, and wherein n is 0 or 1, or a complement thereof.

2. A vector comprising the polynucleotide of claim 1 .

3. A host cell comprising the vector of claim 2 .

4. The polynucleotide of claim 1 , wherein the encoded polypeptide comprises an amino acid sequence selected from the group consisting of KEESIYCRLMGLGCG (SEQ ID NO: 14), NELSPYCRLMGLGCD (SEQ ID NO: 15), NEESMYCRLLGIGCG (SEQ ID NO: 16) and PEESLYCRLLALGCG (SEQ ID NO: 17).

5. The polynucleotide of claim 1 , wherein the encoded polypeptide comprises the amino acid sequence SMYCRLLGIGCG (SEQ ID NO: 18) (BACE031) or ESMYCRLLGIGCG (SEQ ID NO: 19) (BACE030).

6. The polynucleotide of claim 1 , wherein the encoded polypeptide comprises a sequence having cysteines at positions −1 and −8 relative to the C terminus, an arginine or arginine analogue at position −7 relative to the C-terminus, and a leucine at position −6 relative to the C-terminus.

7. The polynucleotide of claim 6 , wherein the encoded polypeptide further comprises small amino acids at positions 0, −2 and −4 relative to the C-terminus, or glycine at positions 0, −2 and −4 relative to the C-terminus, or a hydrophobic residue at position −3 relative to the C-terminus, or a leucine at −5 relative to the C-terminus, or a tyrosine or a phenylalanine at position −9 relative to the C-terminus, or a bulky hydrophobic residue at position −10 relative to the C-terminus, or a serine at position −11 relative to the C-terminus, or an acidic residue at position −12 relative to the C-terminus, or glutamic acid at position −12 relative to the C-terminus.

8. The polynucleotide of claim 6 , wherein the encoded polypeptide comprises amino acids at positions 0, −2 and −4 that are small amino acids; wherein the amino acid at position −3 is a hydrophobic residue; wherein the amino acid at position −5 is leucine or methionine; wherein the amino acid at position −7 is arginine; wherein the amino acid at position −9 is tyrosine or phenylalanine; wherein the amino acid at position −10 is a bulky hydrophobic residue; wherein the amino acid at position −11 is serine; and wherein the amino acid at position −12 is an acidic amino acid.

9. The polynucleotide of claim 8 , wherein the encoded polypeptide comprises amino acids at positions 0, −2 and −4 that are glycines; wherein the amino acid at position −3 is a hydrophobic residue; wherein the amino acid at position −5 is leucine; wherein the amino acid at position −7 is arginine; wherein the amino acid at position −9 is tyrosine; wherein the amino acid at position −10 is a bulky hydrophobic residue; wherein the amino acid at position −11 is serine; and wherein the amino acid at position −12 is glutamic acid.

10. The polynucleotide of claim 6 , wherein the encoded polypeptide comprises a sequence selected from the sequences of BACE binding peptides set forth in Table 2 and FIG. 2 .

11. The polynucleotide of claim 7 , wherein the encoded polypeptide comprises a C terminal amino acid sequence selected from KEESIYCRLMGLGCG (SEQ ID NO: 14), NELSPYCRLMGLGCD (SEQ ID NO: 15), ESMYCRLLGIGCG (SEQ ID NO: 19) and PEESLYCRLLALGCG (SEQ ID NO: 17).

12. The polynucleotide of claim 1 , wherein the encoded polypeptide is an inhibitor of BACE1 proteolytic activity.

Assignees

• Genentech Inc

Inventors

• Lazarus Robert A
• Zhang Yingnan
• Wang Weiru

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P27/06

  Antiglaucoma agents or miotics · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title