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Antiretrovirals inhibit arginase in human microglia
Author(s) -
Lisi Lucia,
Laudati Emilia,
Miscioscia Teresa F.,
Dello Russo Cinzia,
Topai Alessandra,
Navarra Pierluigi
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13393
Subject(s) - arginase , microglia , chemistry , neuroscience , computational biology , virology , medicine , biology , immunology , biochemistry , inflammation , arginine , amino acid
Abstract Preliminary evidence in an animal model, that is, primary cultures of rat microglia cells, suggested that some antiretroviral drugs ( ARV s), 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 ARV s 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 ARV s on CHME ‐5 cell lysates after exposure to the above stimuli. Moreover, the interaction between the ARV s and ARG was investigated via computational chemistry. We found that ARV s 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 ARV s 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.