Abstract
Apoptosis, a morphological distinct form of programmed cell death, is a crucial process during development, the maintenance of cell homeostasis and the regulation of the immune system. A variety of diseases have been found to correlate with physiological apoptosis including cancer, autoimmune disease, viral infection and degenerative disorders.
Although very different signals initiate apoptosis, the phenotype of apoptosis is surprisingly similar even in different cell types suggesting that the final stages of apoptotic death are highly conserved. The execution of the death program is coordinated by a recently identified class of cysteine proteases termed caspases.
The finding that caspases are mainly involved in regulation of this conserved part of the death program has boosted the search for caspase inhibitors which might offer a therapeutic approach to treat apoptitic disorders. Synthetic peptide inhibitors have been developed which exhibit some selectivity for the different caspases. In the last years several natural inhibitors have been discovered which either prevent caspase activation or caspase activity. This review will present the recent advances and discuss the potential of caspase inhibitors as future therapeutics.
Zusammenfassung
Apoptose, eine morphologisch charakteristische Form des programmierten Zelltods, spielt eine bedeutende Rolle während der Entwicklung, bei der Aufrechterhaltung der Zellhomöostase und bei der Regulation des Immunsystems. Eine Reihe von Krankheiten, wie Krebs, Autoimmunerkrankungen, virale Infektionen und degenerative Erkrankungen, wird mit unphysiologischer Apoptose in Verbindung gebracht.
Obwohl die proapoptotischen Signale sehr unterschiedlich sein können, verläuft die Apoptose in unterschiedlichen Zelltypen nach einem überraschend ähnlichen Muster. Diese Beobachtung läßt den Schluß zu, daß die letzte Phase der Apoptose hochkonserviert ist. Das apoptotische Programm wird von einer neuen Klasse von Cysteinproteasen, den Caspasen, koordiniert.
Die Erkenntnis, daß Caspasen an der Regulation des konservierten Teils der Apoptose beteiligt sind, hat die Suche nach Caspaseinhibitoren beflügelt. Diese könnten eine Therapie verschiedener Krankheiten durch Hemmung der Apoptose ermöglichen. So wurden synthetische Peptidinhibitoren entwickelt, die relativ spezifisch die verschiedenen Caspasen hemmen. In den Letzten Jahren wurden mehrere natürliche Caspaseinhititoren entdeckt, die entweder die Aktivierung oder die Aktivität der Caspasen blockieren. Diese Übersichtsarbeit zeigt die neuesten Fortschritte auf und diskutiert das Potential der Caspaseinhibitoren als zukünftige Therapeutika.
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