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Entry inhibitors

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]

HIV entry

Proteins

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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, called a chemokine coreceptor
CXCR4, another chemokine coreceptor 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:

The binding of HIV surface protein gp120 to the CD4 receptor
A conformational change in gp120, which both increases its affinity for a coreceptor and exposes gp41
The binding of gp120 to a coreceptor either CCR5 or CXCR4
The penetration 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."
Enfuvirtide 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 the ability to interact with some component of HIV entry and the possibility 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 trails for FDA approval.
Aplaviroc, an agent similar to maraviroc and vicriroc, clinical trails 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.^[2]
"Next generation fusion inhibitors" are being developed in an attempt to overcome the shortcomings of enfuvirtide. The most promising candidate to date is TRI-1144, in development by Trimeris.^[3]^[4]

References

^ Biswas P, Tambussi G, Lazzarin A (2007). "Access denied? The status of co-receptor inhibition to counter HIV entry". Expert Opin Pharmacother 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538.
^ 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.
^ Mascolini, Mark. Preclinical Work Suggests Advantages of New Fusion Inhibitor Versus Enfuvirtide
^ Next-Generation Fusion Inhibitor Trimeris.com.

v • d • e Antivirals used against HIV (HAART) (primarily J05)
Nucleoside & Nucleotide Reverse Transcriptase Inbitors (NRTI)	Abacavir (ABC) • Didanosine • Emtricitabine° • Lamivudine (3TC)° • Stavudine • Zidovudine (AZT)° • Tenofovir° • Apricitabine^† • Stampidine^† • Elvucitabine^† • Racivir^† • Zalcitabine^‡
Non-Nucleoside Reverse Transcriptase Inhibitiors (NNRTI)	Efavirenz° • Nevirapine • Etravirine^† • Rilpivirine^† • Loviride^‡ • Delavirdine^‡
Protease Inhibitors (PI)	Atazanavir • Darunavir • Fosamprenavir • Lopinavir° • Nelfinavir • Ritonavir • Saquinavir • Tipranavir • Amprenavir^‡ • Indinavir^‡
Entry/fusion inhibitors	Enfuvirtide • Maraviroc • Vicriviroc^† • PRO 140^†
Integrase inhibitors	Raltegravir • Elvitegravir^†
Maturation inhibitors	Bevirimat^† • Vivecon™^†
Combined formulations	Combivir • Atripla • Trizivir • Truvada • Kaletra • Epzicom
Other & experimental agents	Foscarnet • Synergistic enhancers • Epigallocatechin gallate • Portmanteau inhibitors • Globoidnan A • Griffithsin • Diarylpyrimidines • Calanolide A
^†Undergoing clinical trials, not FDA approved. ^‡Formerly or rarely used agent. °Preferred first-line agent.

Categories: Antiretroviral drugs | Inhibitors

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Entry_inhibitors". A list of authors is available in Wikipedia.