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.

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

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]

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. PMID 17472538. doi: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. PMC 2528836Freely accessible. PMID 18519143. doi:10.1016/j.virol.2008.04.032.
  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. PMID 17157668. doi:10.1016/j.jaci.2006.08.016.
  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. PMID 17669213. doi:10.1111/j.1600-0684.2007.00242.x.
  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. PMC 1855571Freely accessible. PMID 17307982. doi:10.1128/AAC.01001-06.
  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. PMC 2453315Freely accessible. PMID 18654624. doi:10.1371/journal.ppat.1000109.
  8. "virionyx.com". Retrieved 2007-08-26.
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