Entry inhibitor

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]

An HIV virion binds to a CD4+ human cell. The two bottom pictures depict two proposed models of HIV fusion with the cell.

HIV entry

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, a 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.

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

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

Approved agents

• Maraviroc (Selzentry in USA, Celsentri in other countries) binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor."^[2]
• Enfuvirtide (Fuzeon) 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 their ability to interact with the proteins involved in HIV entry and the possibility that they may serve as entry inhibitors.^[3]

• TNX-355, a monoclonal antibody that binds CD4 and inhibits the binding of gp120
• PRO 140, a monoclonal antibody that binds CCR5
• Fostemsavir (BMS-663068), 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.^[4]
• 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.^[5]
• 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.^[6]
• CD4 specific Designed Ankyrin Repeat Proteins (DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates ^[7]
• 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.^[8]
• VIR-576 is a synthesized peptide which binds to gp41, preventing fusion of the virus with a cell membrane.

References

1. Biswas P, Tambussi G, Lazzarin A (2007). "Access denied? The status of co-receptor inhibition to counter HIV entry" (abstract page). Expert Opin Pharmacother. 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538.
2. Pugach P, Ketas TJ, Michael E, Moore JP (August 2008). "Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors". Virology. 377 (2): 401–7. doi:10.1016/j.virol.2008.04.032. PMC 2528836. PMID 18519143.
3. Merck Manual.com Human Immunodeficiency Virus (HIV) Infection Table 4
4. Williamson, M.; McCormick, T.; Nance, C.; Shearer, W. (2006). "Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy". Journal of Allergy and Clinical Immunology. 118 (6): 1369–1374. doi:10.1016/j.jaci.2006.08.016. PMID 17157668.
5. Emau P, Tian B, O'keefe BR, et al. (2007). "Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide". J. Med. Primatol. 36 (4–5): 244–53. doi:10.1111/j.1600-0684.2007.00242.x. PMID 17669213.
6. Duong YT, Meadows DC, Srivastava IK, Gervay-Hague J, North TW (May 2007). "Direct inactivation of human immunodeficiency virus type 1 by a novel small-molecule entry inhibitor, DCM205". Antimicrob. Agents Chemother. 51 (5): 1780–6. doi:10.1128/AAC.01001-06. PMC 1855571. PMID 17307982.
7. Schweizer, A; Rusert, P; Berlinger, L; Ruprecht, CR; Mann, A; Corthésy, S; Turville, SG; Aravantinou, M; Fischer, M; Robbiani, M; Amstutz, P; Trkola, A (Jul 25, 2008). "CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.". PLoS Pathogens. 4 (7): e1000109. doi:10.1371/journal.ppat.1000109. PMC 2453315. PMID 18654624.
8. "virionyx.com". Retrieved 2007-08-26.

External links

• Fusion Inhibitor Resource Center
• HIV Fusion Inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)