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Publication
Viral surface glycoproteins as potential drug targets against HIV-1 and HIV-2 infections
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Abstract(s)
AIDS (acquired immune deficiency syndrome) was discovered more than forty years ago, however, until now there is still no vaccine or cure for this disease. AIDS is caused by two human immunodeficiency virus (HIV) types, HIV-1 and HIV-2. HIV-1 is pandemic while HIV-2 is mainly confined to West Africa and western European countries (e. g., France, and Portugal). These two viruses share several common hallmarks, aside from a similar mode of transmission, similar intracellular replication mechanisms, and clinical consequences. In fact, as the disease progresses, people infected with HIV-2 will become vulnerable to the same spectrum of associated opportunistic infections and co-morbidities as people infected with HIV-1. Traditionally, HIV-2 infection is frequently neglected in global HIV/AIDS campaigns, however, a special emphasis must be given to HIV-2, which poses distinct challenges for prevention, diagnosis, and treatment to eradicate AIDS. None of the current drugs effectively prevents entry into the cells and the efficacy of the available drugs is very limited against HIV-2. HIV envelope glycoproteins mediate binding to the receptor CD4 and co-receptors at the surface of the target cell, enabling fusion with the cell membrane and viral entry. The discovery of multiple new hit compounds can be used as useful starting points towards drug candidates for HIV-1 and HIV-2 therapy. The viral gp120 and gp125 are critical for the recognition of receptors and allowing the internalization of viral content into the cell. Its modulation can lead to the disturbance of the entry viral mechanism.
In the absence of a complete crystallographic structure of HIV-2 envelope gp125 comprising variable domains, computer-aided modulation is crucial to identify structural features in the variable regions that correlate with HIV-2 tropism and susceptibility. Here, we developed and optimized a computer-assisted drug design approach of an important HIV-2 glycoprotein that allows us to explore and gain further insights at the molecular level into protein structures and interactions crucial for HIV-2 inhibition. A 3D structure of HIV-2ROD gp125 was generated by a homology modelling campaign. To disclose the importance of the main structural features and compare with experimental results, 3D-models of six mutants were also generated. These mutations revealed selectively impact the behaviour of the protein. Furthermore, molecular dynamics simulations were performed to optimize the models, and the dynamic behavior was tackled into account for structure flexibility and interactions network formation. It is primordial to understand the structural behaviour of these domains inserted in the main structure. Structurally, the mutations studied lead to a loss of aromatic features, very important for the establishment of π-π interactions, which could induce a structural preference by a specific coreceptor. Additionally, a drug discovery protocol to identify small molecules that inhibit the attachment and binding of HIV with host cells mediated by the envelope surface glycoproteins was developed. The discovery protocol based on molecular docking and virtual screening was developed to gp120 of HIV-1 to disclose molecular characteristics of potential new inhibitors of the viral attachment that we want to correlate with the homologous modulated protein of HIV-2.
Altogether, these findings reveal important aspects of the structural characterization of the glycoproteins fundamental to the viral entry mechanism of HIV. The computational approach offers numerous advantages to obtain these new insights into the structure-function relationship, and this translational methodology can lead to the improvement of the knowledge of viral glycoproteins and its application towards the battle against the HIV infection.
Description
Keywords
VIH glicoproteínas virais modelação por homologia dinâmica molecular elucidação estrutural relação estrutura-atividade HIV viral glycoprotein homology modelling molecular dynamics structural elucidation structure-function relationship