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, hepatitis D, and hepatitis B.[1]

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.[2]

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.[3][4]

  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 binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor."[5]
  • 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.
  • Bulevirtide (Hepcludex), is an entry inhibitor that blocks the NTCP receptor on liver cells, preventing Hepatitis B and D viruses from entering. It was granted full marketing authorization by the European Commission in 2023.[6]

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.[7]

  • 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.[8]
  • 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.[9]
  • 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.[10]
  • CD4 specific Designed Ankyrin Repeat Proteins (DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates [11]
  • 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.[12]
  • VIR-576 is a synthesized peptide which binds to gp41, preventing fusion of the virus with a cell membrane.
  • ITX5061 for hepatitis C.[13]

References

  1. ^ "Hepcludex | European Medicines Agency (EMA)". www.ema.europa.eu. 2020-08-12. Retrieved 2026-03-10.
  2. ^ Biswas P, Tambussi G, Lazzarin A (May 2007). "Access denied? The status of co-receptor inhibition to counter HIV entry". Expert Opinion on Pharmacotherapy. 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538. S2CID 32675897.
  3. ^ Xiao, Tianshu; Cai, Yongfei; Chen, Bing (2021). "HIV-1 entry and membrane fusion inhibitors". Viruses. 13 (5): 735. doi:10.3390/v13050735. PMC 8146413. PMID 33922579.
  4. ^ Wilen, Craig B.; Tilton, John C.; Doms, Robert W. (2012). "HIV: cell binding and entry". Cold Spring Harb Perspect Med. 2 (8) a006866. doi:10.1101/cshperspect.a006866. PMC 3405824. PMID 22908191. Retrieved 2021-08-11.
  5. ^ 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.
  6. ^ "ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS" (PDF).
  7. ^ Merck Manual.com Human Immunodeficiency Virus (HIV) Infection Table 4 [1]
  8. ^ Williamson MP, McCormick TG, Nance CL, Shearer WT (December 2006). "Epigallocatechin gallate, the main polyphenol in green tea, binds to the T-cell receptor, CD4: Potential for HIV-1 therapy". The Journal of Allergy and Clinical Immunology. 118 (6): 1369–74. doi:10.1016/j.jaci.2006.08.016. PMID 17157668.
  9. ^ Emau P, Tian B, O'keefe BR, Mori T, McMahon JB, Palmer KE, et al. (August 2007). "Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide". Journal of Medical Primatology. 36 (4–5): 244–53. doi:10.1111/j.1600-0684.2007.00242.x. PMID 17669213. S2CID 22539115.
  10. ^ 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". Antimicrobial Agents and Chemotherapy. 51 (5): 1780–6. doi:10.1128/AAC.01001-06. PMC 1855571. PMID 17307982.
  11. ^ Schweizer A, Rusert P, Berlinger L, Ruprecht CR, Mann A, Corthésy S, et al. (July 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.
  12. ^ "virionyx.com". Retrieved 2007-08-26.
  13. ^ Sulkowski MS, Kang M, Matining R, Wyles D, Johnson VA, Morse GD, et al. (March 2014). "Safety and antiviral activity of the HCV entry inhibitor ITX5061 in treatment-naive HCV-infected adults: a randomized, double-blind, phase 1b study". The Journal of Infectious Diseases. 209 (5): 658–67. doi:10.1093/infdis/jit503. PMC 3923538. PMID 24041792.
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