Natural and Synthetic Inhibitors of Caspases: Targets for Novel Drugs

Author: Brigitte Onteniente

Source: Current Drug Targets-CNS & Neurological Disorders, Volume 3, Number 4, August 2004 , pp. 333-340(8)

Publisher: Bentham Science Publishers

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Abstract:

Along with inflammation, apoptosis appears a common feature of cell death in non-infectious neurodegenerative diseases. The apoptotic program is an energy-requiring, slowly developing process that evolves in three main steps; initiation, progression and execution. Each step of the program is controlled by a number of molecules with synergistic or antagonistic functions, among which the family of cystein proteases called caspases has a primary role. The central position of caspases in all steps of the apoptotic process had led to the development of several families of inhibitory drugs based on the tetrapeptidic sequence of their preferred cleavage site on target molecules. The initial classes of compounds had problems of toxicity, specificity and blood brain barrier penetration, but even so, gave encouraging preclinical results in animal models of neurological diseases. New generations of anti-caspase drugs have been developed, including non peptide-based compounds, which have shown satisfactory pharmaceutical activity. In addition, pre-clinical developments include advances in protein therapy based on the use of natural inhibitors of caspases, which possess the advantage of targeting synergistic neuroprotective pathways. This strategy uses peptidic vectors to carry large molecules through the blood brain barrier and the membrane of brain cells. Although pre-clinical data are compelling, the activity of these various drug families in patients with acute and / or progressive brain lesions has yet to be demonstrated.

Keywords: apoptosis; brain diseases; caspase; caspase inhibitor; neuronal death; recovery of function

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568007043337210

Affiliations: 1: INSERM U421, Universite Paris Val-de-Marne, 8 rue du General Sarrail, 94010 Creteil cedex, France.

Publication date: 2004-08-01

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CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

Natural and Synthetic Inhibitors of Caspases: Targets for Novel Drugs

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