Compounds that regulate apoptosis
Compounds that modulate the function of anti-apoptotic proteins such as Bcl-2 and related Bcl-2 family members are identified. These compounds have the ability to convert the activity of Bcl-2-family member proteins from anti-apoptotic to pro-apoptotic. Methods for inducing or preventing apoptosis are described, together with methods for identifying molecules that induce or prevent apoptosis through interaction with Bcl-2-family members. Methods for treatment of proliferative diseases and neurodegenerative diseases using the modulators of Bcl-2 and related family members are also disclosed.
1. A compound comprising:
a peptide consisting of the sequence of SEQ ID NO:60 or mutation or fragment thereof, wherein the peptide is pro-apoptotic; and
a cell-penetrating-peptide, wherein said compound induces apoptosis of mammalian cells expressing Bcl-2 or Bcl-2 related proteins.
2. The compound of claim 1 , wherein said cell-penetrating peptide comprises transportan 10.
3. The compound of claim 1 , wherein said cell-penetrating peptide consists of penetratin (SEQ ID NO: 65).
4. The compound of claim 1 , wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Gly Asp Trp Ile Asp Ser Ile Leu (SEQ ID NO:16).
5. The compound of claim 1 , wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Ser Arg Ser Leu His Ser Leu Leu (SEQ ID NO:9).
6. The compound of claim 1 , wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Ala Cys Leu Ser Ala Leu Val Leu (amino acid residues 37-45 of SEQ ID NO:60).
7. The compound of claim 1 , wherein the pro-apoptotic fragment consists of the amino acid sequence Phe Tyr Leu Lys Leu Glu Asp Leu Val (SEQ ID NO:18).
8. The compound of claim 1 , wherein the mutation is an amino acid deletion.
9. The compound of claim 1 , wherein the mutation is an amino acid insertion.
10. The compound of claim 1 , wherein the mutation is a conservative amino acid substitution.
11. The compound of claim 1 , wherein the mutation is an amino acid substitution with Alanine.
12. The compound of claim 1 , wherein the mutation is an amino acid substitution with a non-naturally occurring amino acid.
13. The compound of claim 1 , wherein the compound comprises one or more D-amino acids.