title: Anti-apoptotic effect of HIV protease inhibitors via direct inhibition of calpain.
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 mu-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.
authors.affiliation: Dipartimento di Biologia, Universita' di Roma Tor Vergata, via Ricerca Scientifica, 00133 Rome, Italy. ghibelli@uniroma2.it
authors.forename: Lina
authors.initials: L
authors.lastname: Ghibelli
authors.forename: Fabio
authors.initials: F
authors.lastname: Mengoni
authors.forename: Miriam
authors.initials: M
authors.lastname: Lichtner
authors.forename: Simona
authors.initials: S
authors.lastname: Coppola
authors.forename: Milena
authors.initials: M
authors.lastname: De Nicola
authors.forename: Antonio
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Claudio
authors.initials: C
authors.lastname: Mastroianni
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Vullo
mesh_terms: D017209:Apoptosis; D002154:Calpain / Q000037:antagonists & inhibitors*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology
chemical_list: D061945:Caspase Inhibitors; D017320:HIV Protease Inhibitors; D019469:Indinavir; D002154:Calpain; D020169:Caspases; D019438:Ritonavir