title: 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.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Quattrocchi
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cavalli
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Santa
authors.initials: S
authors.lastname: Mammana
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Giuseppe A G
authors.initials: GA
authors.lastname: Lombardo
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pennisi
authors.affiliation: OncoNox, Copenhagen, Denmark.
authors.forename: Mai-Britt
authors.initials: MB
authors.lastname: Zocca
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: He
authors.affiliation: Center for Molecular Innovation, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Al-Abed
authors.affiliation: Department of Biomedical Sciences, University of Catania, Catania, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D003208:Concanavalin A; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D061466:Lopinavir / Q000031:analogs & derivatives / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000031:analogs & derivatives / Q000494:pharmacology*; D019438:Ritonavir / Q000031:analogs & derivatives / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D017320:HIV Protease Inhibitors; D007155:Immunologic Factors; D003208:Concanavalin A; D061466:Lopinavir; D009569:Nitric Oxide; D019438:Ritonavir