Entry and Attachment Inhibitors

Overview

The antiretroviral (ARV) drugs in the entry inhibitor class inhibit viral binding or fusion of HIV to host target cells. When the viral envelope glycoprotein (gp) 120 binds to the CD4 receptor, it induces conformational changes that enable gp120 to interact with a chemokine receptor such as CCR5 or CXCR4 on the host cell. After gp120 binds to the co-receptor, subsequent conformational changes expose the fusion peptide of viral transmembrane gp41. The fusion peptide then inserts into the cell membrane. A helical region of gp41, called HR1, then interacts with a similar helical region, HR2, on gp41. The two helices zip together and mediate 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. The drug binds to the HR1 region, preventing the HR1-HR2 interaction and the 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.

Ibalizumab-uiyk, a recombinant humanized monoclonal antibody, is a CD4-directed post-attachment HIV-1 inhibitor. Ibalizumab-uiyk blocks HIV from infecting CD4+ T cells by binding to domain 2 of CD4, thereby interfering with post-attachment steps required for viral entry and preventing viral transmission that occurs via cell-cell fusion.

Enfuvirtide (Fuzeon, T-20)
Ibalizumab-uiyk (Trogarzo, IBA)
Maraviroc (Selzentry, MVC)