Preliminary evidence in an animal model, i.e. 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. The present 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. This article is protected by copyright. All rights reserved.

Lisi, L., Laudati, E., Miscioscia, T., Dello Russo, C., Topai, A., Navarra, P., Antiretrovirals inhibit arginase in human microglia, <<JOURNAL OF NEUROCHEMISTRY>>, 2016; 136 (Gennaio): 363-372. [doi:10.1111/jnc.13393] [https://hdl.handle.net/10807/91788]

Antiretrovirals inhibit arginase in human microglia

Lisi, Lucia
Primo
;
Laudati, Emilia
Secondo
;
Dello Russo, Cinzia;Navarra, Pierluigi
Ultimo
2016

Abstract

Preliminary evidence in an animal model, i.e. 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. The present 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. This article is protected by copyright. All rights reserved.
2016
Inglese
Lisi, L., Laudati, E., Miscioscia, T., Dello Russo, C., Topai, A., Navarra, P., Antiretrovirals inhibit arginase in human microglia, <<JOURNAL OF NEUROCHEMISTRY>>, 2016; 136 (Gennaio): 363-372. [doi:10.1111/jnc.13393] [https://hdl.handle.net/10807/91788]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/91788
Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 13
  • ???jsp.display-item.citation.isi??? 13
social impact