Natural and synthetic inhibitors of caspases: targets for novel drugs.

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.