Method and compounds for inhibition of cell death
AssigneeUniversity of Central Florida
InventorAntonis Zervos
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Abstract
The invention is directed to methods and compositions for inhibiting caspase-independent apoptosis. In particular, methods and compositions for inhibiting Omi/HtrA2 activity, as well as method for identifying other inhibitors of Omi/HtrA2. Also disclosed are Omi/HtrA2 specific substrates and methods for identifying other substrates of Omi/HtrA2.
Claims53
A pharmaceutical composition for inhibiting cellular apoptosis, the composition comprising at least one apoptosis inhibiting compound that can modulate caspase-independent apoptosis.
A method for inhibiting caspase-independent apoptosis in a cell comprising:
- contacting a cell having Omi/HtrA2 activity with at least one apoptosis inhibiting compound, such that the apoptosis inhibiting compound interacts with Omi/HtrA2 to inhibit the activity of Omi/HtrA2, wherein the inhibition of Omi/HtrA2 activity reduces apoptosis in the cell;
- and
- monitoring the inhibition of apoptosis.
A method of inhibiting Omi/HtrA2 activity, comprising:
- contacting a cell having Omi/HtrA2 activity with an apoptosis inhibiting compound;
- and
- monitoring the inhibition of Omi/HtrA2 activity.
A method for modifying a disorder associated with caspase-independent apoptosis comprising:
- administering a therapeutically effective amount of a composition comprising at least one apoptosis inhibiting compound such that the apoptosis inhibiting compound interacts with Omi/HtrA2 to inhibit the activity of Omi/HtrA2, wherein the inhibition of Omi/HtrA2 activity reduces apoptosis in the cell;
- and
- monitoring the amelioration of the disorder by measuring the change in caspase-independent apoptosis.
A method of preventing tubular cell death, comprising:
- administering an apoptosis inhibiting compound, wherein the apoptosis inhibiting compound interacts with Omi/HtrA2 such that the apoptosis inhibiting compound interacts with Omi/HtrA2 to inhibit the activity of Omi/HtrA2, wherein the inhibition of Omi/HtrA2 activity prevents tubular cell death;
- and
- monitoring the prevention of tubular cell death.
A method for identifying a substrate associated with caspase-independent apoptosis, comprising:
- contacting a cell with recombinant Omi/HtrA2, wherein the recombinant Omi/HtrA2 has proteolytic activity;
- comparing the results of the incubated cell extract with a control sample that has not been incubated with recombinant Omi/HtrA2;
- and
- monitoring a change in the electophoretic mobility of a protein in the cell extract incubated with recombinant Omi/HtrA2, such that a change in electophoretic mobility of the protein indicates that the protein is a substrate of Omi/HtrA2, thereby identifying a substrate associated with caspase-independent apoptosis.
A method for identifying a compound that inhibits caspase-independent apoptosis, comprising:
- contacting the candidate compound with a substrate coupled to a fluorescent marker in the presence of recombinant Omi/HtrA2, wherein the recombinant Omi/HtrA2 has proteolytic activity against the substrate;
- and
- monitoring the change in fluorescence, whereby a candidate compound is identified as being an inhibitor of caspase-independent apoptosis if the candidate compound inhibits or blocks the proteolytic activity of recombinant Omi/HtrA2.
Dependencies are inferred from the claim text.