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ANANBIOANAL - 2010
Inhibitors of Caspases as New Therapeutic Agents
N.Mallikarjuna Rao
Department of Biochemistry,G S L Medical College, Rajahmundry, India
Pharmaceutical R & D Summit
doi:10.4172/2155-9872.1000020
C
aspases are diverse group of enzymes involved in apoptosis and inflammation.
Activation of caspases contributes to large number of pathological conditions
a) Apoptic disorders such as myocardial infarction, lung diseases, liver diseases
and neuronal diseases b) Inflammatory disorders such as rheumatoid arthritis,
osteoarthritis, gout and psoriasis. Inhibition of caspase activity is therapeutically
effective in these disorders. Active site structure based approach, Structure activity
relationship (SAR) based approach, peptidomimetics, high trough put screens (HTS)
and fragment based approach teethering are currently used to discover caspase
inhibitors. Caspases are cysteine proteases containing cysteine at active site and
cleaves-D(Asp)-X-bonds. Active site cysteine and nearby histidine forms catalytic
diad. Binding of negatively charged aspartic acid moiety of the substrate is favoured
by positively charged arginine and glutamine. Catalysis of peptide bond cleavage by
caspase involves formation of tetrahedral transition state thio hemi katal initiated
by active site cysteine acting as nucleophile. Near by histidine residue aids product
release. Inhibition by reversible inhibitors involves formation of thio hemi katal similar
to tetrahedral transition state analog of substrate. A reversible caspase inhibitor
pralancasan (VX-740) is discovered by active site directed approach. Clinical trials
show that pralancasan is an effective anti inflammatory drug. Irreversible caspase
inhibitors forms thio ether adduct resulting in inactivation of enzyme. An irreversible
peptidomimetic inhibitor emricasan (1DN-6556) is designed from di peptide
backbone which is effective in apoptic driven disorders. Isatins, a group of small
molecule inhibitors are identified by high through put screens. Isatins contains a
carbonyl group which is critical for inhibitory activity. Caspases are inactivated due
to interaction of carbonyl group of isatins with active site Cysteine.
ANALBIOANAL-2010
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