The new and less toxic protease inhibitor saquinavir-NO maintains anti-HIV-1 properties in vitro indistinguishable from those of the parental compound saquinavir

Filippo Canducci, Elisa Rita Ceresola, Diego Saita, Yousef Al-Abed, Gianni Garotta, Massimo Clementi, Ferdinando Nicoletti

Research output: Contribution to journalArticlepeer-review

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 (Saq-NO) reduces its toxicity. In this study, we evaluated in vitro the anti-HIV activity of Saq-NO vs. its parental compound Saq. Site directed mutants with the most frequently identified Saq associated resistance mutations and their combinations were generated on proviral AD8-based backbones. Phenotypic assays were conducted using wild type clinical isolates and fully replicating recombinant viruses with Saq and Saq-NO in parallel on purified CD4+ T cells. The following recombinant viruses were generated and tested: L33F, M46I, 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 Saq-NO maintains an anti-HIV-1 profile very similar to that of Saq. The possibility to reduce Saq associated side effects and to increase the concentration of the drug in vivo may allow a higher and possibly more effective dosage of Saq-NO in HIV-1-infected patients and to increase the genetic barrier of this PI thus impairing the selection of resistant clones.

Original languageEnglish
Pages (from-to)292-295
Number of pages4
JournalAntiviral Research
Volume91
Issue number3
DOIs
Publication statusPublished - Sep 2011

Keywords

  • Drug resistance
  • Genetic barrier
  • Protease inhibitors
  • Saquinavir
  • Toxicity

ASJC Scopus subject areas

  • Virology
  • Pharmacology

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