# Entry inhibitor

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 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.

### Proteins

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 and macrophages, called a chemokine co-receptor
* CXCR4, another chemokine co-receptor found on CD4+ cells
* gp41, an HIV protein, closely associated with gp120, that penetrates the cell membrane

### Binding, fusion, entry sequence

HIV entry into a human cell requires the following steps in sequence.
* The binding of HIV surface protein gp120 to the CD4 receptor
* A conformational change in gp120, which both increases its affinity for a co-receptor and exposes gp41
* The binding of gp120 to a co-receptor either CCR5 or CXCR4
* The penetration of the cell membrane by gp41, which approximates the membrane of HIV and the T cell and promotes their fusion
* 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" 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.
* Fostemsavir, an attachment inhibitor that interferes with the interaction of CD4 and gp120 by binding with 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.
* 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.
* 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 (DARPins) 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.
* ITX5061 for hepatitis C.