Entry inhibitors

Entry inhibitors, also known as fusion inhibitors, are a class of antiretroviral drugs, used in combination therapy for the treatment of HIV infection. This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell. By blocking this step in HIV's replication cycle, such agents slow the progression from HIV infection to AIDS.^[1]  

HIV entry

Proteins

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There are several key proteins involved in the HIV entry process.

• 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, called a chemokine coreceptor
• CXCR4, another chemokine coreceptor found on CD4+ cells
• gp41, a HIV protein, closely associated with gp120, that penetrates the cell membrane

Binding, fusion, entry sequence

HIV entry into a human cells requires the following steps in 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 coreceptor and exposes gp41
3. The binding of gp120 to a coreceptor either CCR5 or CXCR4
4. The penetration 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

Entry inhibitors work by interfering with one aspect of this process.

Approved agents

• Maraviroc binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist."
• Enfuvirtide binds to gp41 and interferes with its ability to approximate the two membranes. It is also referred to as a "fusion inhibitor."

Investigation/experimental agents

Other agents are under investigation for the ability to interact with some component of HIV entry and the possibility they may serve as entry inhibitors.

• TNX-355, a monoclonal antibody that binds CD4 and inhibits the binding of gp120
• PRO 140, a monoclonal antibody that binds CCR5
• BMS-488043, a small molecule that interferes with the interaction of CD4 and gp120
• 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 trails for FDA approval.
• Aplaviroc, an agent similar to maraviroc and vicriroc, clinical trails 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.^[2]
• "Next generation fusion inhibitors" are being developed in an attempt to overcome the shortcomings of enfuvirtide. The most promising candidate to date is TRI-1144, in development by Trimeris.^[3][4]

References