Advances in HIV-1 Entry Inhibitors: Strategies to Interfere with Receptor and CoReceptor Engagement

The present armamentarium of 19 antiretroviral drugs licensed for treatment of HIV-1 infection in the U.S. exemplifies preponderance of scientific evidence, which led to improved understanding of the structural and functional, viral and cellular attributes driving HIV-1 infection. The majority of approved drugs (with exception of enfuvirtide), however, focus on two steps of the viral life cycle: reverse transcription and viral maturation. Therefore, it appears there is ample opportunity for the development of a third drug class that has been extensively researched in recent years known as entry inhibitors. Currently, this class of compounds targets steps involved in virion attachment to CD4 or to an appropriate chemokine receptor on the cell surface as well as subsequent conformational rearrangements induced in the envelope glycoprotein (gp120/gp41; Env). These inhibitors preclude the fusion of the virion envelope with the host cell membrane thereby preventing the release of viral capsid into the cytosol. Antiviral agents interfering with receptor (i.e., CD4) or coreceptor (e.g., CCR5 and/or CXCR4) engagement comprise a special subset of viral entry inhibitors. While drugs targeting viral entry offer certain advantages over other classes of compounds, they also pose specific challenges. This review focuses on compounds blocking viral attachment to CD4, CCR5 or CXCR4, highlights the challenges they present, and attempts to offer possible solutions.