Treatment with drugs designed to inhibit the HIV protease ameliorates immune functions in AIDS patients, reducing cell deletion by apoptosis even in the absence of inhibition of viral spread. This suggests that they interact with the intrinsic apoptotic signaling. We found that caspases. the main executioner of the apoptotic process, are not directly inhibited. In search for the mechanism responsible for their anti-apoptotic effect, we have found that indinavir and ritonavir are able to inhibit apoptosis only in those cell systems where apoptosis involves the activation of calpains. They directly inhibit a calpain-like activity expressed in lysates from apoptotic cells, to the same extent as commercially available calpain inhibitor 1. In in vitro assays with purified calpains, indinavir and ritonavir strongly inhibit m-calpain, and moderately p-calpain. These results have great therapeutic implications, going beyond AIDS treatment, since many degenerative disorders involve abnormal calpain activation, indicating calpain as an ideal pharmacological target. Indinavir and ritonavir, potent m-calpain inhibitors, largely used since several years on humans without important negative side effects, may become powerful tools against those pathologies. (C) 2003 Published by Elsevier Inc.

Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain / Lina, Ghibelli; Fabio, Mengoni; Lichtner, Miriam; Simona, Coppola; M., De Nicola; Antonio, Bergamaschi; Mastroianni, Claudio Maria; Vincenzo, Vullo. - In: BIOCHEMICAL PHARMACOLOGY. - ISSN 0006-2952. - 66:8(2003), pp. 1505-1512. ((Intervento presentato al convegno 5th International Conference on Apoptosis from Signalling Pathways to Therapeutic Tools tenutosi a LUXEMBOURG, LUXEMBOURG nel JAN 29-FEB 01, 2003 [10.1016/s0006-2952(03)00505-7].

Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain

LICHTNER, Miriam;MASTROIANNI, Claudio Maria;
2003

Abstract

Treatment with drugs designed to inhibit the HIV protease ameliorates immune functions in AIDS patients, reducing cell deletion by apoptosis even in the absence of inhibition of viral spread. This suggests that they interact with the intrinsic apoptotic signaling. We found that caspases. the main executioner of the apoptotic process, are not directly inhibited. In search for the mechanism responsible for their anti-apoptotic effect, we have found that indinavir and ritonavir are able to inhibit apoptosis only in those cell systems where apoptosis involves the activation of calpains. They directly inhibit a calpain-like activity expressed in lysates from apoptotic cells, to the same extent as commercially available calpain inhibitor 1. In in vitro assays with purified calpains, indinavir and ritonavir strongly inhibit m-calpain, and moderately p-calpain. These results have great therapeutic implications, going beyond AIDS treatment, since many degenerative disorders involve abnormal calpain activation, indicating calpain as an ideal pharmacological target. Indinavir and ritonavir, potent m-calpain inhibitors, largely used since several years on humans without important negative side effects, may become powerful tools against those pathologies. (C) 2003 Published by Elsevier Inc.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/254414
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