Virus Entry as a Target for Anti-HIV Intervention
Jose A. Este.
The replicative cycle of the human immunodeficiency virus (HIV) can be interrupted at several stages. Until recently only the viral reverse transcriptase and protease were the only enzymes targeted by antiretroviral agents. However, the first HIV entry inhibitor (T-20, Enfuvirtide, Fuseon) to be used in humans has been approved by the Food and Drug Administration (FDA). The HIV entry process is considered as an attractive target for chemotherapeutic intervention, as blocking HIV entry into its target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell contacts. HIV-1 entry into target cells is a multistep process: virus attachment is initiated by the binding of trimeric envelope glycoprotein gp120 complexes on the virions to glycosylated T-cell surface receptor (CD4) and HIV GPCR coreceptors (CCR5 or CXCR4) leading to envelope glycoprotein gp41-dependent fusion-pore formation and membrane fusion. A number of compounds are being developed to specifically target each of these steps leading to virus entry and some compounds have reached early clinical development. Conversely, agents such as the CCR5 antagonist Tak-779 and the CXCR4 antagonist AMD3100 are not longer being thought as relevant anti-HIV agents but have given way to new analogues with improved properties. This review summarizes the current state of HIV entry inhibitors, their mechanisms of action and their therapeutic value against HIV infection and AIDS.
Keywords: hiv, aids, entry ihibitors, fusion, antivirals, drug development
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