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CASPASES: Keys in the Ignition of Cell Death

Jean-Bernard Denault and Guy S. Salvesen


Chem Rev. 2002 ,102(12):4489-500

Simer Mann M. Pharm (Semester -1) Pharmaceutical Chemistry

CASPASESCYSTEINE ASPARTATE SPECIFIC PROTEASES


Highly specific cysteine proteases Cleave proteins exclusively after aspartate residues Sequence of 3 amino acids before aspartate determines substrate specificity Regulate proteolysis during apoptotic cell death

Useful in cancer therapy

APOPTOSIS ?
Cleavage of proteins in a caspase dependent manner

Loss of Function

Gain of Function

Proteolysis of poly(ADP-ribose) polymerase implicated in DNA repair Inhibition of caspase activated DNAase that causes DNA fragmentation SnRNP implicated in RNA splicing Golgi reassembly and stacking protein

Removal of negative regulating domain: Protein kinase C activation and ROCK I activation implicated in membrane blebbing and apoptotic body formation

INITIATION OF APOPTOSIS

CASPASE TYPES: BASED ON SEQUENCE OF


ACTIVATION IN APOPTOSIS
Initiator (Activator) caspases Caspase 2,8,9,10 First to be activated on commitment of cell to die Activated initiator caspases: Cleave & activate effector caspases Prodomains: Long; Contain regulatory sequences Effector (Executioner) caspases Caspase 3,6,7 Cleave & activate cellular substrates Prodomains: Short; No known regulatory sequences Cytokine processors (Inflammatory) Caspase 1,4,5,11,12,13,14 Caspase 1 is cytokine activator Prodomains: Long; Contain regulatory sequences

http://neuromuscular.wustl.edu/mother/apoptosis.htm#apoptosis

CASPASE INHIBITORS
Inhibitors act as pseudosubstrates for active caspases Modified tetra- or tripeptide pseudo substrates with cleavage sequence of the caspase target coupled with an aldehyde or ketone group Ketones are irreversible inhibitors which bind at enzymatic center of caspase Aldehydes are reversible/competitive caspases inhibitors Carboxy-terminal O-phenoxy group with an aminoterminal quinolyl group improves efficacy

J. Cell. Mol. Med. Vol 8, No 4, 2004 pp. 432-444 Caspases: potential targets for regulating cell death -A. Philchenkov

Cysteine Protease mediated Cleavage of Peptide Bond

PAN-CASPASE INHIBITOR Z-VAD.FMK

H N

O N H

CH3

H N

O F CO2CH3

O H3C CH3

Decreases level of apoptosis in animals with acute lung injury, nephrotoxic nephritis, subarachnoid haemorrhage, and heart failure after a myocardial infarction Reduced inflammation and prolongation of the survival rate in diseased animals was also evident. J. Cell. Mol. Med. Vol 8, No 4, 2004 pp. 432-444 Caspases: potential targets for regulating cell death -A. Philchenkov

RECENT ADVANCES IN PEPTIDOMIMETIC CASPASE INHIBITORS


Caspase inhibitor DEVD-CHO Q-VD-Oph zVAD-FMK Source Synthetic peptidic Synthetic peptidic Synthetic peptidic Target caspase(s) Strong inhibitor of caspase 3 and caspase 7 Caspases 1, 3, 8 & 9 Inhibits all caspases, but inhibits caspase 2 very weakly Broad spectrum irreversible caspase inhibition Caspase 1 Reversible, selective effector caspase inhibitor Targets allosteric site rather than active site

IDN-6556 Pralnacasan M867 Compound 34

Synthetic non-peptide, Idun (Pfizer)


Synthetic non-peptide (Vertex) Synthetic non-peptide (Merck-Frosst) Synthetic non-peptide (Sunesis)

Emerging therapeutic targets in Caspase dependent disease- Christopher B.Mc Bride

CASPASE ACTIVATORS
Lowering activation threshold helps combat cancer in apoptosis deficiency pathogenesis Pharmacologically-active caspase activator MX-2060 Caspase activators are peptides containing arginineglycine-aspartate (RGD) Cancer gene therapy is carried with inducible caspase-1, -3 or -9 molecules ,activated on demand in vivo by addition of cell-permeable chemical inducers of dimerization Compound K (obtained from Panax ginseng)-stimulates apoptosis via the activation of caspase-3 and caspase-9 activation.

J. Cell. Mol. Med. Vol 8, No 4, 2004 pp. 432-444 Caspases: potential targets for regulating cell death -A. Philchenkov

STAUROSPORINE
H N
Apoptosis Inducer Activates Caspase- 3 Causes cell death within 3 hours

N O

N H

O HN

Staurosporine binds to the ATP binding pocket of many kinases inhibiting their activity

CONCLUSION
Proteases seem to be potential targets for therapeutic interventions Inhibition of caspases deliver therapy in ischemic damage or neurodegenerative diseases Cancer therapy relies on the combined application of apoptosis-sensitizing strategies and conventional radioand chemotherapy Caspase inhibitors have broad spectrum of activity