Autophagy-inducing peptide analogs

1. An autophagy-inducing compound comprising an autophagy-inducing 9, 10 or 11-mer peptide of Beclin 1, and no more of Beclin 1 than the 9, 10 or 11-mer peptide, the peptide comprising Beclin 1 residue 269 or 270 to Beclin 1 residue 278 or 279, wherein Beclin 1 residues 269-279 is VFNATFHIWHS (SEQ ID NO:01), wherein up to six of said residues may be substituted, and wherein:

(a) F270 and F274 are substituted or linked;

(b) the peptide is cyclized;

(c) the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain, a homing peptide, or a serum stabilizing agent; or

(d) the peptide comprises a sequence, unsubstituted, selected from:

Peptide

Sequence

SEQ ID NO

Mutant 1

C FNATFEIWHD

SEQ ID NO: 10;

Mutant 2

V W NATFEIWHD

SEQ ID NO: 11;

Mutant 3

VF D ATFEIWHD

SEQ ID NO: 12;

Mutant 4

VFN S TFEIWHD

SEQ ID NO: 13;

Mutant 5

VFNA C FEIWHD

SEQ ID NO: 14;

Mutant 6

VFNAT W EIWHD

SEQ ID NO: 15;

Mutant 7

VFNATF D IWHD

SEQ ID NO: 16;

Mutant 8

VFNATFE L WHD

SEQ ID NO: 17;

Mutant 9

VFNATFEI F HD

SEQ ID NO: 18;

Mutant 10

VFNATFEIW Y D

SEQ ID NO: 19;

Mutant 11

VFNATFEIWH E

SEQ ID NO: 20;

Mutant 12

V W NATFE L WHD

SEQ ID NO: 21;

Mutant 13

V Y NATFEIWHD

SEQ ID NO: 22;

Mutant 14

VFNATFE V WHD

SEQ ID NO: 23;

Mutant 15

V L NATFEIWHD

SEQ ID NO: 24;

Mutant 16

VFNATFE M WHD

SEQ ID NO: 25;

Mutant 17

V W NATF H IWHD

SEQ ID NO: 26;

Mutant 18

VFNATFE F WHD

SEQ ID NO: 27;

Mutant 19

VFNATFE Y WHD

SEQ ID NO: 28;

Mutant 20

VFNATFE R WHD

SEQ ID NO: 29;

Mutant 21

FNATFEIWHD

SEQ ID NO: 30;

Mutant 25

VFNATFEIWH

SEQ ID NO: 31;

Mutant 26

 FNATFEIWH

SEQ ID NO: 32;

Mutant 27

  W NATF H IWH

SEQ ID NO: 33;

Mutant 28

V W NATF H IWH

SEQ ID NO: 34; and

Mutant 29

  W NATF H IWHD

SEQ ID NO: 35.

2. The compound of claim 1 wherein the peptide comprises a sequence, unsubstituted, selected from:

Peptide

Sequence

SEQ ID NO

Mutant 1

C FNATFEIWHD

SEQ ID NO: 10;

Mutant 2

V W NATFEIWHD

SEQ ID NO: 11;

Mutant 3

VF D ATFEIWHD

SEQ ID NO: 12;

Mutant 4

VFN S TFEIWHD

SEQ ID NO: 13;

Mutant 5

VFNA C FEIWHD

SEQ ID NO: 14;

Mutant 6

VFNAT W EIWHD

SEQ ID NO: 15;

Mutant 7

VFNATF D IWHD

SEQ ID NO: 16;

Mutant 8

VFNATFE L WHD

SEQ ID NO: 17;

Mutant 9

VFNATFEI F HD

SEQ ID NO: 18;

Mutant 10

VFNATFEIW Y D

SEQ ID NO: 19;

Mutant 11

VFNATFEIWH E

SEQ ID NO: 20;

Mutant 12

V W NATFE L WHD

SEQ ID NO: 21;

Mutant 13

V Y NATFEIWHD

SEQ ID NO: 22;

Mutant 14

VFNATFE V WHD

SEQ ID NO: 23;

Mutant 15

V L NATFEIWHD

SEQ ID NO: 24;

Mutant 16

VFNATFE M WHD

SEQ ID NO: 25;

Mutant 17

V W NATF H IWHD

SEQ ID NO: 26;

Mutant 18

VFNATFE F WHD

SEQ ID NO: 27;

Mutant 19

VFNATFE Y WHD

SEQ ID NO: 28;

Mutant 20

VFNATFE R WHD

SEQ ID NO: 29;

Mutant 21

FNATFEIWHD

SEQ ID NO: 30;

Mutant 25

VFNATFEIWH

SEQ ID NO: 31;

Mutant 26

FNATFEIWH

SEQ ID NO: 32;

Mutant 27

W NATF H IWH

SEQ ID NO: 33;

Mutant 28

V W NATF H IWH

SEQ ID NO: 34; and

Mutant 29

W NATF H IWHD

SEQ ID NO: 35.

3. The compound of claim 1 wherein the peptide comprises the sequence VWNATFHIWHD (SEQ ID NO:26).

4. The compound of claim 1 , wherein the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain, a homing peptide, or a serum stabilizing agent.

5. The compound of claim 1 , wherein the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain that is:

a protein-derived cell-penetrating peptide selected from tat, smac, pen, pVEC, bPrPp, PIs1, VP22, M918 and pep-3;

a chimeric cell-penetrating peptide selected from TP, TP10 and MPGΔ; or

a synthetic cell-penetrating peptide selected from MAP, Pep-1, and oligo Arg.

6. The compound of claim 1 , wherein the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain that is a protein-derived cell-penetrating peptide that is tat.

7. The compound of claim 1 , wherein the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain that is a synthetic cell-penetrating peptide that is oligo Arg.

8. The compound of claim 1 , wherein the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain that is a protein-derived cell-penetrating peptide that is tat, or a synthetic cell-penetrating peptide that is oligo Arg, and the peptide is C-terminally flanked by moiety R 2 , and R 2 is carboxyl or R 2 comprises an affinity tag or detectable label.

9. The compound of claim 1 , wherein the peptide is N-terminally flanked through a diglycine linker.

10. The compound of claim 1 wherein the peptide is C-terminally flanked by moiety R 2 , and R 2 is carboxyl or R 2 comprises an affinity tag or detectable label.

11. The compound of claim 1 wherein the peptide is C-terminally flanked by moiety R 2 , and R 2 is carboxyl.

12. The compound of claim 1 , wherein:

the peptide comprises the sequence VWNATFHIWHD (SEQ ID NO:26);

the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain that is a protein-derived cell-penetrating peptide that is tat;

the peptide is N-terminally flanked through a diglycine linker; and

the peptide is C-terminally flanked by moiety R 2 , and R 2 is carboxyl.

13. The compound of claim 1 , wherein:

the peptide comprises the sequence VWNATFHIWHD (SEQ ID NO:26);

the peptide is N-terminally flanked by moiety R 1 , and R 1 comprises a transduction domain that is a synthetic cell-penetrating peptide that is oligo Arg;

the peptide is N-terminally flanked through a diglycine linker; and

the peptide is C-terminally flanked by moiety R 2 , and R 2 is carboxyl.

14. The compound of claim 1 wherein F270 and/or F274 are substituted or linked.

15. The compound of claim 1 wherein:

a) F270 and F274 are substituted with crosslinkable moieties and/or linked, and each optionally comprises an additional α-carbon substitution selected from substituted, optionally hetero-lower alkyl, particularly optionally substituted, optionally hetero-methyl, ethyl, propyl and butyl; or

b) F270 and F274 are substituted with homocysteines connected through a disulfide bridge to generate a ring and tail cyclic peptide.

16. The compound of claim 1 wherein side chains of F270 and F274 are replaced by a linker:

—(CH 2 ) n ONHCOX(CH 2 ) m —, wherein X is CH 2 , NH or O, and m and n are integers 1-4, forming a lactam peptide;

—CH 2 OCH 2 CHCHCH 2 OCH 2 —, forming an ether peptide; or

—(CH 2 ) n CHCH(CH 2 ) m —, forming a stapled peptide.

17. The compound of claim 1 wherein the peptide is cyclized.

18. The compound of claim 1 wherein:

1 to 6 residues are alanine substituted;

the peptide comprises at least one of substitutions: H275E and S279D; or

the peptide comprises one or more D-amino acids, L-β-homo amino acids, D-β-homo amino acids, or N-methylated amino acids;

the peptide is acetylated, acylated, formylated, amidated, phosphorylated, sulfated or glycosylated; or

the compound comprises an N-terminal acetyl, formyl, myristoyl, palmitoyl, carboxyl or 2-furosyl group, and/or a C-terminal hydroxyl, amide, ester or thioester group.

19. A pharmaceutical composition comprising a compound of claim 1 in unit dosage, administrable form.

20. A method of inducing autophagy, comprising administering to a person in need thereof an effective amount of a compound of claim 1 .