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08:47
Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
Published on: March 5, 2018
Allosteric peptides bind a caspase zymogen and mediate caspase tetramerization
Karen Stanger1, Micah Steffek, Lijuan Zhou
1Department of Early Discovery Biochemistry, Genentech, South San Francisco, California, USA.
Nature Chemical Biology
|June 12, 2012
Summary
Researchers developed a novel strategy to inhibit caspase-6 by screening its inactive zymogen form. This approach identified a peptide that allosterically impairs caspase-6 function, offering a promising new avenue for drug discovery in neurodegenerative diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Caspases are crucial proteases involved in inflammation and apoptosis.
- Targeting caspase active sites for drug development has faced significant challenges.
- Caspase-6 is a potential therapeutic target for neurodegenerative disorders.
Purpose of the Study:
- To develop a new strategy for inhibiting caspase-6.
- To identify novel inhibitors by screening the zymogen form of caspase-6.
- To explore an allosteric mechanism for caspase inhibition.
Main Methods:
- Phage display screening was employed to identify molecules binding to zymogen caspase-6.
- In vitro assays were used to assess the functional impact of identified peptides.
- Experiments were conducted in neuronal cells to evaluate efficacy.
Main Results:
- A peptide specifically binding to zymogen caspase-6 was identified.
- This peptide was shown to impair caspase-6 function both in vitro and in neuronal cells.
- The peptide binds to a unique tetramerization interface on the zymogen, not the active site.
- The mechanism of inhibition involves promoting caspase tetramerization via allosteric regulation.
Conclusions:
- Screening against the zymogen form is a viable strategy for developing caspase inhibitors.
- This new allosteric approach offers a promising alternative to active-site-directed drug discovery.
- The identified peptide represents a potential therapeutic lead for targeting caspase-6 in neurodegenerative diseases.
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