Entry Inhibitors

Overview

The antiretroviral (ARV) drugs in this class inhibit viral binding or fusion of HIV to host target cells. Binding of the viral envelope glycoprotein (gp)120 to the CD4 receptor induces conformational changes that enable gp120 to interact with a chemokine receptor such as CCR5 or CXCR4 on the host cell; binding of gp120 to the co-receptor causes subsequent conformational changes in the viral transmembrane gp41, exposing the fusion peptide of gp41, which inserts into the cell membrane. A helical region of gp41, called HR1, then interacts with a similar helical region, HR2, on gp41, resulting in a zipping together of the 2 helices and mediating the fusion of cellular and viral membranes. Enfuvirtide, which requires subcutaneous (SQ) administration, is a synthetic 36-amino-acid peptide derived from a naturally occurring motif within the HR2 domain of viral gp41, and the drug binds to the HR1 region, preventing the HR1-HR2 interaction and correct folding of gp41 into its secondary structure, thereby inhibiting virus-cell fusion. Maraviroc is a CCR5 co-receptor antagonist that interferes with viral entry at the chemokine co-receptor level.