title: Interactions between integrase inhibitors and human arginase 1.
abstract: The neuro-pathogenic mechanism(s) underlying HIV-associated neurocognitive disorders are mostly unknown. HIV-infected macrophages and microglial cells play a crucial role and the metabolic fate of l-arginine may be highly relevant to microglia activation. In this context, arginase (ARG), which uses l-arginine as substrate, can be on the same time a target and source of oxidative stress and inflammation. In this study, we investigated whether integrase strand transfer inhibitors share with the other antiretroviral drugs the ability to inhibit ARG activity. We used the previously validated cell model, namely the human microglia cell line, as well as the computational chemistry approach. Furthermore, here we characterized the activity of purified human ARG in a cell-free in vitro system, and investigated the effects of integrase strand transfer inhibitors in this newly validated model. Overall evidence shows that Dolutegravir, Raltegravir and Elvitegravir inhibit ARG activity.
authors.affiliation: Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Lisi
authors.affiliation: Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pizzoferrato
authors.affiliation: Colosseum Combinatorial Chemistry Centre for Technology, Rome, Italy.
authors.forename: Fabiola Teresa
authors.initials: FT
authors.lastname: Miscioscia
authors.affiliation: Colosseum Combinatorial Chemistry Centre for Technology, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Topai
authors.affiliation: Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Pierluigi
authors.identifier: 0000-0002-4424-650X
authors.initials: P
authors.lastname: Navarra
mesh_terms: D015526:AIDS Dementia Complex / Q000201:enzymology / Q000378:metabolism; D001119:Arginase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002474:Cell-Free System; D002478:Cells, Cultured; D019428:HIV Integrase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D062105:Molecular Docking Simulation; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones / Q000494:pharmacology; D000068898:Raltegravir Potassium / Q000494:pharmacology; D000099226:Dolutegravir
chemical_list: D001119:Arginase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D015363:Quinolones; D000068898:Raltegravir Potassium; D000099226:Dolutegravir; C509700:elvitegravir; C574619:ARG1 protein, human
keywords: arginase 1; integrase strand transfer inhibitors; microglia