Effects of NO-Hybridization on the Immunomodulatory Properties of the HIV Protease Inhibitors Lopinavir and Ritonavir.

Abstract

HIV protease inhibitors (PIs) are antiretroviral agents, which have been found to also affect several cellular processes, such as inflammation and cell progression. In studies on non-steroidal, anti-inflammatory drugs, the addition of a nitric oxide (NO) moiety has been shown to both reduce their toxicity and enhance their pharmacological efficacy. Along this line of research, several derivatives of PIs have been synthesized by covalent attachment of NO moiety to the parental molecules. Previous work has indicated that NO-hybridization of the prototypical PI, Saquinavir leads to a derivative named Saquinavir-NO that while retaining the antiretroviral effect, acquires antitumoural and immunomodulatory properties along with reduced toxicity in vitro and in vivo. These data prompted us to evaluate the effects of NO-hybridization on two other PIs, Lopinavir and Ritonavir. The two NO-derivatives were compared head to head with their parental compounds on human primary peripheral blood mononuclear cells as well as on human primary macrophages. Lopinavir-NO and Lopinavir were also screened in an in vivo model of autoimmune hepatitis. Our results prove that Lopinavir-NO exerts markedly superior effects as compared to the parental compound both in vitro and in vivo. On the contrary, Ritonavir-NO effects overlapped those of Ritonavir. These data demonstrate that NO-hybridization of Lopinavir generates a derivative with significantly stronger immunomodulatory effects that are apparently related to an action of the compound on T-cell secretory capacity. Lopinavir-NO deserves additional studies for its possible use in T-cell-mediated autoimmune diseases including, but not limited to autoimmune hepatitis.

• Authors: Paolo Fagone, Katia Mangano, Cinzia Quattrocchi, Eugenio Cavalli, Santa Mammana, Giuseppe A G Lombardo, Vincenzo Pennisi, Mai-Britt Zocca, Mingzhu He, Yousef Al-Abed, Ferdinando Nicoletti
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 117 Issue 5 Pg. 306-15 (Nov 2015) ISSN: 1742-7843 [Electronic] England
• PMID: 25903922 (Publication Type: Comparative Study, Journal Article)
• Copyright: © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Chemical References

• Cytokines
• HIV Protease Inhibitors
• Immunologic Factors
• Concanavalin A
• Lopinavir
• Nitric Oxide
• Ritonavir

Topics

• Animals
• Concanavalin A
• Cytokines (immunology, metabolism)
• Disease Models, Animal
• Drug Design
• Female
• HIV Protease Inhibitors (pharmacology)
• Hepatitis, Autoimmune (drug therapy, immunology)
• Humans
• Immunologic Factors (pharmacology)
• Leukocytes, Mononuclear (drug effects, immunology, metabolism)
• Lopinavir (analogs & derivatives, pharmacology)
• Macrophages (drug effects, immunology, metabolism)
• Mice
• Nitric Oxide (analogs & derivatives, pharmacology)
• Ritonavir (analogs & derivatives, pharmacology)
• T-Lymphocytes (drug effects, immunology)