Entry inhibitor

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 cells 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 coreceptor and exposes gp41
  3. The binding of gp120 to a coreceptor 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 (Celsentri) 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.

  • TNX-355, a monoclonal antibody that binds CD4 and inhibits the binding of gp120
  • PRO 140, a monoclonal antibody that binds CCR5
  • BMS-488043, a small molecule that interferes with the interaction of CD4 and gp120
  • 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.[3]
  • 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.[4]
  • CD4 specific Designed Ankyrin Repeat Proteins (DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates [5]

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. http://www.expertopin.com/doi/abs/10.1517/14656566.8.7.923. 
  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. http://linkinghub.elsevier.com/retrieve/pii/S0042-6822(08)00272-9. 
  3. ^ 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. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0047-2565&date=2007&volume=36&issue=4-5&spage=244. 
  4. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1855571. 
  5. ^ Schweizer, A; Rusert, P, Berlinger, L, Ruprecht, CR, Mann, A, Corthésy, S, Turville, SG, Aravantinou, M, Fischer, M, Robbiani, M, Amstutz, P, Trkola, A (2008 Jul 25). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2453315. 

External links

v · d · eAntiviral drugs: antiretroviral drugs used against HIV (primarily J05)
Entry/fusion inhibitors
(Discovery & development)
gp41 (Enfuvirtide) • CCR5 (Maraviroc, Vicriviroc†, Cenicriviroc†, PRO 140†) • CD4 (Ibalizumab†)
Reverse-transcriptase
inhibitors (RTIs)

Nucleoside analogues/NARTIs: Abacavir (ABC)°# • Emtricitabine (FTC)°# • Lamivudine (3TC)°# • Didanosine (ddI)# • Zidovudine (AZT)# • Apricitabine† • Stampidine† • Elvucitabine† • Racivir† • Amdoxovir†• Stavudine (d4T)# • Zalcitabine (ddC)◊ • Festinavir† 

Nucleotide analogues/NtRTIs: Tenofovir°#
Non-Nucleoside (NNRTI)
(Discovery & development)
(1st generation) Efavirenz°# • Nevirapine#  • Loviride◊ • Delavirdine◊ •
 (2nd generation) diarylpyrimidines (Etravirine, Rilpivirine)  • Lersivirine†
Integrase inhibitors
Raltegravir • Elvitegravir† • Dolutegravir† • Globoidnan A (experimental)  • MK-2048†  • BI 224436†  
Maturation inhibitors
Bevirimat† • Vivecon†
Protease Inhibitors (PI)
(Discovery and development)
1st generation
Fosamprenavir° • Lopinavir°# • Nelfinavir# • Ritonavir# • Saquinavir# • Amprenavir◊ • Indinavir◊#
2nd generation
Combined formulations
Lamivudine/zidovudine • Emtricitabine/tenofovir/efavirenz • Abacavir/lamivudine/zidovudine • Tenofovir/emtricitabine • Lopinavir/ritonavir • Abacavir/lamivudine • Emtricitabine/rilpivirine/tenofovir
Experimental agents
TRIM5alpha (gene)
Tat antagonists
Trichosanthin
Other
Failed agents
Dexelvucitabine • Capravirine • Emivirine • Lodenosine • Atevirdine • Brecanavir • Aplaviroc
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III °DHHS preferred first-line agent. ◊Formerly or rarely used agent.

M: VIR

virs(prot)/clss

cutn/syst (hppv/hiva, infl/zost/zoon)/epon

drugJ(dnaa, rnaa, rtva, vacc)



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