title: Antiretrovirals inhibit arginase in human microglia.
abstract: Preliminary evidence in an animal model, that is, primary cultures of rat microglia cells, suggested that some antiretroviral drugs (ARVs), namely darunavir, atazanavir, efavirenz, and nevirapine, increase NO production through a mechanism involving the inhibition of arginase (ARG) activity. This study was conceived to investigate the effects of ARVs on ARG activity in a human experimental model. We compared CHME-5 human microglial immortalized cells under basal conditions with cells exposed to either IL-4, a mix of inflammatory cytokines, or both stimuli given together. We also tested the effects of ARVs on CHME-5 cell lysates after exposure to the above stimuli. Moreover, the interaction between the ARVs and ARG was investigated via computational chemistry. We found that ARVs consistently inhibit ARG activity both in intact and lysed cells. In docking studies, darunavir and atazanavir showed similar scores compared with both l-arginine and the ARG antagonist nor-NOHA. Efavirenz and nevirapine, which are less potent in inhibiting ARG in the biochemical assay, also had lower scores. In conclusion, the present findings in a human model support the notion that ARG pathway can present a new, additional molecular target for different ARVs in HIV treatments. We found that antiretroviral drugs (ARVs) consistently inhibit arginase (ARG)-I activity both in intact and lysed cells. In docking studies, darunavir (DRV) and atazanavir (ATV) showed similar scores compared to both l-arginine and the ARG antagonist, Nω-hydroxy-nor-arginine (nor-NOHA). Efavirenz (EFV) and nevirapine (NVP), which are less potent in inhibiting ARG in the biochemical assay, also had lower scores. In conclusion, the present findings in a human model support the notion that ARG pathway can be envisioned as an additional and new molecular target of different ARVs in HIV treatments.
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: Emilia
authors.initials: E
authors.lastname: Laudati
authors.affiliation: Colosseum Combinatorial Chemistry Centre for Technology, Rome, Italy.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Miscioscia
authors.affiliation: Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Dello Russo
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.initials: P
authors.lastname: Navarra
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D001119:Arginase / Q000378:metabolism*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology*; D008958:Models, Molecular; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014508:Urea / Q000378:metabolism
chemical_list: D044966:Anti-Retroviral Agents; D009573:Nitrites; D012333:RNA, Messenger; D014508:Urea; D052247:Nitric Oxide Synthase Type II; D001119:Arginase
keywords: ARG; antiretroviral drugs; arginase-I; microglia; microglial polarization