Caspase inhibitors - A chemist's perspective

Article type: Research Article

Authors: Graczyk, Piotr P.

Affiliations: Department of Medicinal Chemistry, EISAI London Research Laboratories University College London, Bernard Katz Building, London WC1E 6BT UK. Tel.: + 44 171 388 4746; Fax: + 44 171 413 1121; E-mail: [email protected]

Abstract: Contribution of apoptotic mechanisms to neurodegeneration is an emerging concept. Caspases which are activated during apoptotic cell death may serve as an attractive target of pharmacological intervention. Caspase inhibitors include proteins, peptides, peptidomimetics and various small molecules. Peptide conjugates with quinones, epoxyquinones and epoxyquinols which constitute new types of pharmaeophores exhibit submicromolar activity against caspase-3 and show moderate neuroprotective effects on neuronal cells. Peptide-derived inhibitors may suffer from insufficient cell membrane permeability. However, double ester-type prodrugs may offer an option to transport a peptide-like inhibitor across the cell membrane. These developments may lead to identification of novel neuroprotective drugs.

Keywords: neurodegeneration, apoptosis, caspase inhibitors, quinones, epoxyquinones, epoxyquinols, prodrugs

Journal: Restorative Neurology and Neuroscience, vol. 14, no. 1, pp. 1-23, 1999