Although, the antiviral activity, tolerability and convenience of protease inhibitors have improved significantly in recent years, toxicity-associated adverse events including diarrhea, lipid alterations, disturbance of glucose homeostasis and liver enzyme elevations still remain a major concern during treatment of HIV-1 patients. We have recently shown that the covalent attachment of the NO moiety to the HIV-1 protease inhibitor saquinavir (Sag-NO) reduces its toxicity. In this study, we evaluated in vitro the anti-HIV activity of Sag-NO vs. its parental compound Sag. Site directed mutants with the most frequently identified Sag associated resistance mutations and their combinations were generated on proviral ADS-based backbones. Phenotypic assays were conducted using wild type clinical isolates and fully replicating recombinant viruses with Saq and Sag-NO in parallel on purified CD4+ T cells. The following recombinant viruses were generated and tested: L33F, M461, G48V, I54V, I84V + L90M, M46I + L90M, G48V + L90M, M46I + I54V + L90M, L33F + M46I + L90M. The fold change resistance compared to the wild type viruses was between 1.3 and 7 for all single mutants, between 3.4 and 20 for double mutants and between 16.7 and 28.5 for viruses carrying three mutations for both compounds. The results clearly demonstrate that Sag-NO maintains an anti-HIV-1 profile very similar to that of Sag. The possibility to reduce Sag associated side effects and to increase the concentration of the drug in vivo may allow a higher and possibly more effective dosage of Sag-NO in HIV-1-infected patients and to increase the genetic barrier of this PI thus impairing the selection of resistant clones. (C) 2011 Elsevier B.V. All rights reserved.
The new and less toxic protease inhibitor saquinavir-NO maintains anti-HIV-1 properties in vitro indistinguishable from those of the parental compound saquinavir
NICOLETTI, FERDINANDO
2011-01-01
Abstract
Although, the antiviral activity, tolerability and convenience of protease inhibitors have improved significantly in recent years, toxicity-associated adverse events including diarrhea, lipid alterations, disturbance of glucose homeostasis and liver enzyme elevations still remain a major concern during treatment of HIV-1 patients. We have recently shown that the covalent attachment of the NO moiety to the HIV-1 protease inhibitor saquinavir (Sag-NO) reduces its toxicity. In this study, we evaluated in vitro the anti-HIV activity of Sag-NO vs. its parental compound Sag. Site directed mutants with the most frequently identified Sag associated resistance mutations and their combinations were generated on proviral ADS-based backbones. Phenotypic assays were conducted using wild type clinical isolates and fully replicating recombinant viruses with Saq and Sag-NO in parallel on purified CD4+ T cells. The following recombinant viruses were generated and tested: L33F, M461, G48V, I54V, I84V + L90M, M46I + L90M, G48V + L90M, M46I + I54V + L90M, L33F + M46I + L90M. The fold change resistance compared to the wild type viruses was between 1.3 and 7 for all single mutants, between 3.4 and 20 for double mutants and between 16.7 and 28.5 for viruses carrying three mutations for both compounds. The results clearly demonstrate that Sag-NO maintains an anti-HIV-1 profile very similar to that of Sag. The possibility to reduce Sag associated side effects and to increase the concentration of the drug in vivo may allow a higher and possibly more effective dosage of Sag-NO in HIV-1-infected patients and to increase the genetic barrier of this PI thus impairing the selection of resistant clones. (C) 2011 Elsevier B.V. All rights reserved.File | Dimensione | Formato | |
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