Cell penetrating peptides which bind irf5

Patent metadata

Field	Value
Publication number	US-2016009772-A1
Application number	US-201314432977-A
Country	US
Kind code	A1
Filing date	Oct 7, 2013
Priority date	Oct 8, 2012
Publication date	Jan 14, 2016
Grant date	—

Abstract

The present invention comprises cell penetrating peptides that bind to interferon regulatory factor IRF5 and disrupt the IRF5 homo-dimerization and/or attenuate downstream signaling, and a method for screening peptides that inhibit IRF5. Generally, the cell penetrating peptides of the invention bind human interferon regulatory factor IRF5 (CPP-IRF5).

First claim

1 . A cell-penetrating peptide which binds interferon regulatory factor IRF5 (CPP-IRF5), wherein the peptide comprises an amino acid sequence of 20 to 40 amino acids and wherein said amino acid sequence further comprises, in part, an amino acid sequence motif selected from the group consisting of:
a) I-x-L-x-I-S-x-P-x-x-K (SEQ ID NO: 30), wherein
I isisoleucine,
L is leucine,
S is serine,
P is proline,
K is lysine, and
x is independently selected from any amino acid; or
b) Y-R1-R2-R3-R8-R4-R5-R9 (SEQ ID NO: 31), wherein
Y is tyrosine,
R1 is an amino acid selected from the group of tryptophan (W) or alanine (A),
R2 is an amino acid selected from the group consisting of leucine (L) or threonine (T),
R3 is an amino acid selected from the group consisting of leucine (L), alanine (A), aspartic acid (D), phenylalanine (F), or tyrosine (Y),
R8 is leucine (L),
R4 is an amino acid selected from the group consisting of leucine (L), glycine (G) or threonine (T),
R5 is an amino acid selected from the group consisting of phenylalanine (F), leucine (L) or methionine (M), and
R9 is valine (V) or leucine (L); or
c) K-D-R6-M-V-R7-F-K-D (SEQ ID NO: 2), wherein
K is lysine,
D is aspartic acid,
R6 is an amino acid selected from the group consisting of leucine or aspartic acid,
M is methionine,
R7 is selected from the group consisting of Glutamine-Tryptophan (Q-W) and arginine-phenylalanine (R-F), and
F is phenylalanine;
or a pharmaceutically acceptable salt thereof.

2 . The CPP-IRF5 peptide according to claim 1 , wherein the peptide comprises an amino acid sequence of 20 to 40 amino acids and wherein said amino acid sequence further comprises, in part, an amino acid sequence motif selected from the group consisting of:
a) Y-R1-R2-R3-L-R4-R5-V (SEQ ID NO: 1), wherein
Y is tyrosine,
R1 is an amino acid selected from the group of tryptophan (W) or alanine (A),
R2 is an amino acid selected from the group consisting of leucine (L) or threonine (T),
R3 is an amino acid selected from the group consisting of leucine (L), alanine (A), aspartic acid (D), or phenylalanine (F),
L is leucine,
R4 is an amino acid selected from the group consisting of leucine (L), glycine (G) or threonine (T),
R5 is an amino acid selected from the group consisting of phenylalanine (F), leucine (L) or methionine (M), and
V is valine; or
b) K-D-R6-M-V-R7-F-K-D (SEQ ID NO: 2), wherein
K is lysine,
D is aspartic acid,
R6 is an amino acid selected from the group consisting of leucine or aspartic acid,
M is methionine,
R7 is selected from the group consisting of Glutamine-Tryptophan (Q-W) and arginine-phenylalanine (R-F), and
F is phenylalanine;
or a pharmaceutically acceptable salt thereof.

3 . The CPP-IRF5 peptide according to claim 1 , wherein the peptide comprises an amino acid sequence of 20 to 35 amino acids.

4 . The CPP-IRF5 peptide according to claim 1 , wherein the amino acid sequence motif is I-x-L-x-I-S-x-P-x-x-K (SEQ 1D NO: 30), wherein x is as defined in claim 1 .

5 . The CPP-IRF5 peptide according to any of claim 1 , wherein the amino acid sequence motif is Y-R1-R2-R3-R8-R4-R5-R9 (SEQ ID NO: 31), wherein R1, R2, R3, R4, R5, R8 and R9 are as defined in claim 1 .

6 . The CPP-IRF5 peptide according to claim 1 , wherein the amino acid sequence motif is Y-R1-R2-R3-L-R4-R5-V (SEQ ID NO: 1), wherein R1, R2, R3, R4 and R5 are as defined in claim 2 .

7 . The CPP-IRF5 peptide according to claim 1 , wherein the amino acid sequence motif is MANLG-Y-R1-R2-R3-L-R4-R5-V (SEQ ID NO: 3), wherein M is methionine, A is alanine, N is asparagine, L is leucine, G is glycine, Y is tyrosine, V is valine and R1, R2, R3, R4, and R5 are as defined in claim 1 .

8 . The CPP-IRF5 peptide according to claim 1 , wherein the amino acid sequence motif is MANLG-Y-R1-R2-R3-L-R4-R5-V (SEQ ID NO: 3), wherein M is methionine, A is alanine, N is asparagine, L is leucine, G is glycine, Y is tyrosine, V is valine and R1, R2, R3, R4, and R5 are as defined in claim 2 .

9 . The CPP-IRF5 peptide according to claim 1 , wherein the amino acid sequence motif is K-D-R6-M-V-R7-F-K-D (SEQ ID NO: 2), wherein R6 and R7 are as defined in claim 2 .

10 . The CPP-IRF5 peptide according to claim 1 , additionally comprising a second peptide which is a cell penetrating peptide (CPP).

11 . The CPP-IRF5 peptide according to claim 1 , additionally comprising an N-terminal modification, a C-terminal modification or both.

12 . The CPP-IRF5 peptide according to claim 1 , additionally comprising an N-terminal modification selected from acetylation, a C-terminal modification selected from amidation or both.

13 . The CPP-IRF5 peptides according to claim 1 , wherein the peptides comprise an amino acid sequence selected from the group consisting of:

SEQ ID NO 13:

IRLQISNPYLKFIPLKRAIWLIK,

SEQ ID NO 14:

MIILIISFPKHKDWKVILVK,

SEQ ID NO 4:

MANLGYWLLLLFVTMWTDVGLAKKRPKP,

SEQ ID NO 5:

MANLGYWLALLFVTMWTDVGLFKKRPKP,

SEQ ID NO 8:

KDLMVQWFKDGGPSSGAPPPS,

SEQ ID NO 9:

IRLQISNPDLKDLMVQWFKDGGPSSGAPPPS,

and

SEQ ID NO 10:

PFPPLPIGEEAPKDDMVRFFKDLHQYLNVV.

14 . A cell-penetrating peptide which binds interferon regulatory factor IRF5 (CPP-IRF5), wherein the peptide comprises an amino acid sequence of 20 to 40 amino acids selected from the group consisting of:

SEQ ID NO 6:

MANLGYWLLALFVTYWTDLGLVKKRPKP,

SEQ ID NO 7:

MANLGYWLYALFLTMVTDVGLFKKRPKP,

or a pharmaceutically acceptable salt thereof.

15 . The CPP-IRF5 peptides according to claim

Assignees

• Hoffmann La Roche

Inventors

• Demartino Julie
• Fotouhi Nader
• Hoffman Ann
• Huang Kuo-Sen
• Milletti Francesca
• Panicker Sandip
• Srinivasan Dinesh
• Tan Seng-Lai

Classifications

• A61P37/02

  Immunomodulators · CPC title

• G01N2500/04

  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 title

• G01N21/6428

  Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" (in vivo A61B5/00; immunoassay G01N33/53) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• G01N33/6872

  Intracellular protein regulatory factors and their receptors, e.g. including ion channels · CPC title