BH4 stabilized peptides and uses thereof
Provided herein are polypeptides containing stabilized BH4 domains of BCL-2 family proteins that are capable of binding and/or inactivating and/or modulating BAX protein, and/or its close homologs BAK and BOK, and/or other physiological BH4 targets. Also provided are compositions containing these polypeptides and methods of treating cytotoxic diseases that include administering to a subject one of the polypeptides.
1. An internally cross-linked polypeptide comprising the amino acid sequence of EIVMKYIHYKLSQRGYEWDA (SEQ ID NO: 1),
wherein:
the side chains of amino acid residues at positions 8 and 12 of SEQ ID NO: 1 or the side chains of amino acid residues at positions 13 and 17 of SEQ ID NO: 1 are replaced by an internal staple; and
the internally cross-linked polypeptide is capable of specifically binding to a BAX protein; and
optionally, the amino acid residue at position 4 of SEQ ID NO: 1 is substituted with another amino acid.
2. The cross-linked polypeptide of claim 1 , wherein the side chains of amino acid residues 13 and 17 of SEQ ID NO: 1 are replaced by an internal staple.
3. A pharmaceutical composition comprising one or more of the cross-linked polypeptides of claim 1 .
4. A kit for identifying agents that interact with and/or modulate the activity of BAX protein comprising one or more of the cross-linked polypeptides of claim 1 and a polypeptide comprising the amino acid sequence of a BAX polypeptide.
5. A compound comprising one or more of the cross-linked polypeptides of claim 1 .
6. The cross-linked polypeptide of claim 1 , wherein the side chains of the amino acid residues at positions 8 and 12 of SEQ ID NO: 1 are replaced by an internal staple.