Selective Bfl-1 peptides

1. A compound comprising a peptide comprising the amino acid sequence:

F1 G1 A2 B2 C2 D2 E2 F2 G2 A3 B3 C3 D3 E3 F3 G3 A4 B4 C4 D4 E4 F4 G4 (SEQ ID NO:1), wherein:

F1 is Q or is missing;

G1 is W, G, 4, 4-biphenylalanine, azidoalanine, or is missing;

A2 is A, V, or I;

B2 is R;

C2 is E, H, or 2,3-diaminopropanoic acid;

D2 is I, norleucine, homoleucine, cyclohexylalanine, 2-aminoheptanoic acid, or 2,4-diaminobutyric acid;

E2 is G, or A;

F2 is A or Y;

G2 is Q, G, D, or E;

A3 is L, cyclohexylalanine, or homoleucine;

B3 is R;

C3 is R, or L;

D3 is M, A, F, d-phenylglycine, d-histidine, d-leucine, α-aminoisobutyric acid, or cyclohexanecarboxylic acid;

E3 is A, ornithine, 2,4-diaminobutyric acid, or 2,3-diaminopropanoic acid;

F3 is D or homoglutamate;

G3 is D, N, I or a conservative substitution;

A4 is L, V, or d-cyclohexylalanine;

B4 is N;

C4 is A;

D4 is Q;

E4 is Y, L, or V;

F4 is E;

G4 is R;

provided that A2, E2, G2, C3, D3, G3, A4 and E4 are not simultaneously A, G, Q, R, M, D, L and Y respectively.

2. The compound of claim 1 , wherein F1 is Q or is missing; G1 is W, G, or is missing; A2 is V or I; B2 is R; C2 is E, H, or 2,3-diaminopropanoic acid; D2 is I or 2,4-diaminobutyric acid; E2 is A; F2 is A or Y; G2 is G, D, or E; A3 is L; B3 is R; C3 is L or R; D3 is A or F; E3 is A; F3 is D; G3 is N, D or I; A4 is L or V; B4 is N; C4 is A; D4 is Q; E4 is L or V; F4 is E; and G4 is R.

3. The compound of claim 1 , wherein an electrophilic group is attached to the N-terminus of the peptide via an amide bond.

4. The compound of claim 3 , wherein the electrophilic group is an acrylamide.

5. The compound of claim 1 , wherein A2 is V, E2 is A, G2 is G, C3 is L, D3 is A, G3 is N, A4 is V and E4 is L.

6. The compound of claim 1 , wherein A2 is V, E2 is A, G2 is G, D3 is A, A4 is V and E4 is V.

7. The compound of claim 1 , wherein A2 is I, E2 is A, G2 is G, D3 is F, G3 is I and E4 is V.

8. The compound of claim 4 , wherein an acrylamide is attached to the amino terminus of the polypeptide via an amide bond.

9. The compound of claim 1 , wherein a cell penetrating peptide tag or an affinity tag is attached to the peptide.

10. A compound comprising a peptide comprising an amino acid sequence selected from:

(SEQ ID NO: 6)

QWAREIGAQLRRIVIADDLNAQVER;

(SEQ ID NO: 7)

QWVREIAAGLRRAADDVNAQYER;

(SEQ ID NO: 8)

QWVREIAAQLRRIVIADDLNAQYER;

(SEQ ID NO: 9)

QWAREIGAGLRRAADDVNAQVER;

(SEQ ID NO: 10)

GVREIAYGLRRAADDVNAQVER;

(SEQ ID NO: 11)

GVRHIAYGLRRAADDVNAQVER;

(SEQ ID NO: 12)

GVRHIAYDLRRAADDVNAQVER;

(SEQ ID NO: 13)

GVRHIAYELRRAADDVNAQVER;

(SEQ ID NO: 14)

GVR2IAYGLRRAADDVNAQVER; 

and

(SEQ ID NO: 15)

GVRE3AYGLRRAADDVNAQVER;

wherein 2 is 2,3-Diaminopropanoic acid, and 3 is 2,4-diaminobutyric acid.

11. A method for detecting a Bfl-1-dependent cancer cell, comprising:

permeabilizing the cancer cell;

contacting the cancer cell with any one of the compounds of claim 1 ;

measuring the mitochondrial depolarization of the cancer cell; and

detecting a Bfl-1-dependent cancer cell when the mitochondrial depolarization is increased as compared to a control cancer cell that has not been contacted by the compound.

12. A method of detecting Bfl-1-induced resistance to chemotherapeutics in a cancer cell, comprising:

permeabilizing the cancer cell;

contacting the cancer cell with any one of the compounds of claim 1 ;

measuring the mitochondrial depolarization of the cancer cell; and

detecting Bfl-1-induced resistance to chemotherapeutics when the mitochondrial depolarization is increased as compared to a control cancer cell that has not been contacted by the compound.

13. A method for detecting overexpression of Bfl-1 in a cancer cell, comprising:

permeabilizing the cancer cell;

contacting the cancer cell with any one of the compounds of claim 1 ; and

measuring the mitochondrial depolarization of the cancer cell; and

detecting overexpression of Bfl-1 when the mitochondrial depolarization is increased as compared to a control cancer cell that has not been contacted by the compound.

14. A method for detecting a Bfl-1-dependent cancer cell, comprising:

permeabilizing the cancer cell;

contacting the cancer cell with any one of the compounds of claim 10 ,

measuring the mitochondrial depolarization of the cancer cell; and

detecting a Bfl-1-dependent cancer cell when the mitochondrial depolarization is increased as compared to a control cancer cell that has not been contacted by the compound.

15. A method of detecting Bfl-1-induced resistance to chemotherapeutics in a cancer cell, comprising:

permeabilizing the cancer cell;

contacting the cancer cell with any one of the compounds of claim 10 ;

measuring the mitochondrial depolarization of the cancer cell; and

detecting Bfl-1-induced resistance to chemotherapeutics when the mitochondrial depolarization is increased as compared to a control cancer cell that has not been contacted by the compound.

16. A method for detecting overexpression of Bfl-1 in a cancer cell, comprising:

permeabilizing the cancer cell;

contacting the cancer cell with any one of the compounds of claim 10 ,

measuring the mitochondrial depolarization of the cancer cell; and

detecting overexpression of Bfl-1 when the mitochondrial depolarization is increased as compared to a control cancer cell that has not been contacted by the compound.