Compositions and method for regulating apoptosis
AssigneeThe Trustees of Princeton University
InventorYigong Shi
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Abstract
Peptides and peptidomimetics capable of modulating apoptosis through their interaction with cellular IAPs (inhibitor of apoptosis proteins) are disclosed. The peptides and mimetics are based on the N-terminal tetrapeptide of IAP-binding proteins, such as Smac/DIABLO, Hid, Grim and Reaper, which interact with a specific surface groove of IAP. Also disclosed are methods of using these peptides and peptidomimetics for therapeutic purposes and for rational drug design.
Claims14
A composition comprised of a peptidomimetic of a tetrapeptide having sequence X1-X2-X3-X4 wherein
- X1 is A,
- X2 is selected from the group consisting of V, T, and I,
- X3 is selected from the group consisting of P and A,
- X4 is selected from the group consisting of F, Y, I and V, and
- wherein said peptidomimetic is capable of binding a BIR-3 domain of an Inhibitor of Apoptosis Protein (IAP), wherein at least one of the amino acids is replaced with a modified amino acid, or at least one of the peptide bonds is replaced with a peptide bond substitute, and wherein the binding within a surface groove of the BIR-3 domain of the IAP is affected.
A compound that binds a BIR-3 domain of an Inhibitor of Apoptosis Protein (IAP) and relieves IAP mediated inhibition of caspase activity, the compound having a formula R1-R2-R3-R4, wherein
- R1 is A or a mimetic of A;
- R2 is V, T or I, or a mimetic of V, T or I;
- R3 is P or A, or a mimetic of P or A;
- R4 is F, Y, I or V, or a mimetic of F, Y, I or V;
- and
- wherein said peptidomimetic is capable of binding a BIR-3 domain of an Inhibitor of Apoptosis Protein (IAP), wherein at least one of the amino acids is replaced with a modified amino acid, or at least one of the peptide bonds is replaced with a peptide bond substitutes, and wherein the binding within a surface groove of the BIR-3 domain of the IAP is affected.
Dependencies are inferred from the claim text.