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Published on: August 15, 2012
Modelling interaction between HIV-1 Nef and calnexin
Alexei A Adzhubei1,2, Anastasia A Anashkina1, Yaroslav V Tkachev1
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Insights
Researchers modeled the interaction between HIV Nef and calnexin, identifying compounds that inhibit this interaction. An analog of a tested compound effectively reversed Nef
Area of Science:
- Molecular biology and virology
- Drug discovery and medicinal chemistry
- Cardiovascular research
Background:
- HIV-associated atherosclerosis is a significant comorbidity linked to the virus's impact on cholesterol metabolism.
- The HIV protein Nef disrupts the maturation of ATP-Binding Cassette (ABCA) 1, a key cellular cholesterol transporter.
- Nef interferes with ABCA1 maturation by binding to and impairing the function of calnexin, an endoplasmic reticulum chaperone.
Purpose of the Study:
- To model the interaction interface between HIV Nef and calnexin.
- To identify small molecule compounds capable of inhibiting the Nef-calnexin interaction.
- To explore therapeutic strategies for HIV-associated comorbidities.
Main Methods:
- Molecular dynamics simulations were used to model the calnexin cytoplasmic domain.
- Global docking and QASDOM software were employed for receptor-ligand complex analysis.
- Structure-based virtual screening identified potential inhibitory compounds, with one analog tested in vitro.
Main Results:
- Key interaction sites between calnexin and Nef were identified.
- Virtual screening revealed small molecules that could block the calnexin interaction site.
- A Nef inhibitor analog, AMS-55, effectively reversed Nef's negative impact on ABCA1 levels.
Conclusions:
- The study successfully modeled the Nef-calnexin interaction and identified potential inhibitors.
- Experimental validation confirmed the effectiveness of a novel inhibitory compound.
- These findings offer a basis for developing new treatments for HIV-related cardiovascular issues.
Background:
HIV-associated atherosclerosis is a major comorbidity due, in part, to systemic effects of the virus on cholesterol metabolism. HIV protein Nef plays an important role in this pathology by impairing maturation of the main cellular cholesterol transporter ATP-Binding Cassette (ABCA) 1. ABCA1 maturation critically depends on calnexin, an integral endoplasmic reticulum membrane chaperone, and Nef binds to the cytoplasmic domain of calnexin and impairs interaction of calnexin with ABCA1. Overarching goal of the present study was to model Nef-calnexin interaction interface, and identify small molecule compounds potentially inhibiting this interaction.
Methods:
Molecular dynamics was utilized to build structure model of calnexin cytoplasmic domain, followed by global docking combined with application of QASDOM software developed by us for efficient analysis of receptor-ligand complexes. Structure-based virtual screening was performed for all sites identified by docking. A soluble analogue of a compound from the screening results list was tested for ability to down-regulate ABCA1.
Results:
We identified major interaction sites in calnexin and reciprocal sites in Nef. Virtual screening yielded a number of small-molecule compounds potentially blocking a calnexin site. Interestingly, one of the compounds, NSC13987, was previously identified by us as an inhibitor targeting a Nef site. An analogue of NSC13987, AMS-55, potently reversed the negative effect of Nef on ABCA1 abundance.
Conclusions:
We have modelled Nef-calnexin interaction, predicted small molecule compounds that can potentially inhibit this interaction, and experimentally tested one of these compounds, confirming its effectiveness. These findings provide a platform for searching for new therapeutic agents to treat HIV-associated comorbidities.
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