Entry inhibitor

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Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D.

HIV entry

They are used in

There are several key proteins involved in the HIV entry process.^{[citation needed]}

• 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
• gp120, that penetrates the cell membrane

HIV entry into a human cell requires the following steps in sequence.[2]^[3]

1. The binding of HIV surface protein
   gp120
   to the CD4 receptor
2. A
   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

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

Approved agents

• gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor."^[4]
• 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.
• gp120
  .

Investigational agents

Other agents are under investigation for their ability to interact with the proteins involved in HIV entry and the possibility that they may serve as entry inhibitors.^[5]

• Leronlimab, a monoclonal antibody that binds CCR5
• Plerixafor was being developed to interfere with interaction between HIV and CXCR4, but showed little useful antiviral activity in recent trials.
• gp120 as do several other theaflavins.^[6]
• 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
  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.^[7]
• 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.^[8]
• CD4 specific Designed Ankyrin Repeat Proteins (DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates ^[9]
• 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.^[10]
• VIR-576 is a synthesized peptide which binds to gp41, preventing fusion of the virus with a cell membrane.
• ITX5061 for hepatitis C.^[11]

References