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Allosteric Tuning of Caspase-7: a Fragment-Based Drug Discovery Approach.

08:00 EDT 22nd September 2017 | BioPortfolio

Summary of "Allosteric Tuning of Caspase-7: a Fragment-Based Drug Discovery Approach."

The caspase family of cysteine proteases are highly sought after drug targets due to their essential roles in apoptosis, proliferation and inflammation pathways. High throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful tool for the discovery of innovative drug leads. This methodology has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors. An X-ray crystal structure of caspase-7 bound to a fragment hit, and a thorough kinetic characterization of a zymogenic form of the enzyme are used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes, and provides a new path forward for drug discovery efforts.

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This article was published in the following journal.

Name: Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
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Medical and Biotech [MESH] Definitions

A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 7; CASPASE 8; and CASPASE 10. Isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A short pro-domain caspase that plays an effector role in APOPTOSIS. It is activated by INITIATOR CASPASES such as CASPASE 3 and CASPASE 10. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Activation of this enzyme can occur via the interaction of its caspase recruitment domain with CARD SIGNALING ADAPTOR PROTEINS. Caspase 2 plays a role in APOPTOSIS by cleaving and activating effector pro-caspases. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA.

A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Caspase 9 is activated by pro-apoptotic factors that are released during cell stress and by CARD SIGNALING ADAPTOR PROTEINS. It activates APOPTOSIS by cleaving and activating EFFECTOR CASPASES.

An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.

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