Entry inhibitor

HIV entry

Proteins

• CD4, a protein receptor found on the surface of helper T cells in the human immune system, also called CD4+ T cells
• gp120, a protein on HIV surface that binds to the CD4 receptor
• CCR5, a second receptor found on the surface of CD4+ cells and macrophages, called a chemokine co-receptor
• CXCR4, another chemokine co-receptor found on CD4+ cells
• gp41, a HIV protein, closely associated with gp120, that penetrates the cell membrane

  Binding, fusion, entry sequence

1. The binding of HIV surface protein gp120 to the CD4 receptor
2. A conformational change in gp120, which both increases its affinity for a co-receptor and exposes gp41
3. The binding of gp120 to a co-receptor either CCR5 or CXCR4
4. The penetration of the cell membrane by gp41, which approximates the membrane of HIV and the T cell and promotes their fusion
5. The entry of the viral core into the cell

Approved agents

• Maraviroc binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor."
• Enfuvirtide binds to gp41 and interferes with its ability to approximate the two membranes. It is also referred to as a "fusion inhibitor."
• Ibalizumab, a monoclonal antibody that binds to domain 2 of CD4 and interferes with post-attachment steps required for the entry of HIV-1 virus particles into host cells and prevents the viral transmission that occurs via cell-cell fusion.

  Investigation agents

• PRO 140, a monoclonal antibody that binds CCR5
• Fostemsavir, an attachment inhibitor that interferes with the interaction of CD4 and gp120 by binding with it.
• Plerixafor was being developed to interfere with interaction between HIV and CXCR4, but showed little useful antiviral activity in recent trials.
• Epigallocatechin gallate, a substance found in green tea, appears to interact with gp120 as do several other theaflavins.
• Vicriviroc, similar to maraviroc, is currently undergoing clinical trials for FDA approval.
• Aplaviroc, an agent similar to maraviroc and vicriroc. Clinical trials were halted in 2005 over concerns about the drug's safety.
• b12 is an antibody against HIV found in some long-term nonprogressors. It has been found to bind to gp120 at the exact region, or epitope, where gp120 binds to CD4. b12 seems to serve as a natural entry inhibitor in some individuals. It is hoped that further study of b12 may lead to an effective HIV vaccine.
• Griffithsin, a substance derived from algae, appears to have entry inhibitor properties.
• DCM205, is a small molecule based on L-chicoric acid, an integrase inhibitor. DCM205 has been reported to inactivate HIV-1 particles directly in vitro and is thought to act primarily as an entry inhibitor.
• CD4 specific Designed Ankyrin Repeat Proteins potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates
• A polyclonal caprine antibody is in phase II human clinical trials that targets, among others sites, the GP41 transmembrane glycoprotein. The trials are being conducted by Virionyx, a New Zealand Company.
• VIR-576 is a synthesized peptide which binds to gp41, preventing fusion of the virus with a cell membrane.