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Entry inhibitors, also known asfusion inhibitors, are a class ofantiviral drugs that prevent avirus from entering acell, for example, by blocking areceptor. Entry inhibitors are used to treat conditions such asHIV andhepatitis D.

They are used incombination therapy for the treatment ofHIV infection. This class of drugs interferes with thebinding, fusion and entry of an HIVvirion to a human cell. By blocking this step inHIV's replication cycle, such agents slow the progression from HIV infection toAIDS.^[1]

There are several keyproteins involved in theHIV entry process.^{[citation needed]}

• CD4, a protein receptor found on the surface ofhelper 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 achemokine co-receptor
• CXCR4, another chemokine co-receptor found on CD4+ cells
• gp41, an HIV protein, closely associated withgp120, that penetrates thecell membrane

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

1. The binding of HIV surface proteingp120 to the CD4 receptor
2. Aconformational change ingp120, which both increases its affinity for a co-receptor and exposesgp41
3. The binding ofgp120 to aco-receptoreither CCR5 or CXCR4
4. The penetration of thecell membrane by gp41, which approximates the membrane of HIV and theT cell and promotes their fusion
5. The entry of theviral core into the cell

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

• Maraviroc binds toCCR5, preventing an interaction withgp120. 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, amonoclonal 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 andgp120 by binding withgp120.

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.
• Epigallocatechin gallate, a substance found ingreen tea, appears to interact withgp120 as do several othertheaflavins.^[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 anantibody against HIV found in somelong-term nonprogressors. It has been found to bind togp120 at the exact region, orepitope, wheregp120 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 directlyin vitro and is thought to act primarily as an entry inhibitor.^[8]
• CD4 specific DesignedAnkyrin Repeat Proteins (DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates^[9]
• A polyclonalcaprine antibody is in phase II humanclinical 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 forhepatitis C.^[11]

• Fusion Inhibitor Resource Center
• HIV+Fusion+Inhibitors at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Entry inhibitors

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