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Interactions between integrase inhibitors and human arginase 1
Lucia Lisi1, Michela Pizzoferrato1, Fabiola Teresa Miscioscia2
1Institute of Pharmacology, Catholic University Medical School, Rome, Italy.
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.
Insights
Integrase strand transfer inhibitors like Dolutegravir, Raltegravir, and Elvitegravir can inhibit arginase activity. This finding may offer new insights into managing HIV-associated neurocognitive disorders by targeting microglia activation.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- The mechanisms behind HIV-associated neurocognitive disorders are largely unknown.
- HIV-infected macrophages and microglia are key players, with l-arginine metabolism potentially influencing microglia activation.
- Arginase (ARG) utilizes l-arginine and is implicated in oxidative stress and inflammation.
Purpose of the Study:
- To investigate if integrase strand transfer inhibitors (INSTIs) inhibit arginase (ARG) activity.
- To explore the potential of INSTIs as modulators of ARG activity in the context of HIV neuroinflammation.
Main Methods:
- Utilized a validated human microglia cell line model.
- Employed computational chemistry approaches.
- Characterized purified human ARG activity in a cell-free in vitro system.
- Assessed the effects of specific INSTIs on ARG activity.
Main Results:
- Dolutegravir, Raltegravir, and Elvitegravir demonstrated inhibition of arginase activity.
- The study validated a new cell-free in vitro system for studying ARG inhibitors.
Conclusions:
- Integrase strand transfer inhibitors show potential in inhibiting arginase activity.
- These findings contribute to understanding the neuroprotective effects of certain antiretroviral drugs.
- Targeting arginase may be a viable strategy in addressing HIV-associated neurocognitive disorders.