Introduction to Enfuvirtide (Fuzeon)
Enfuvirtide, marketed under the brand name Fuzeon, marked a significant advancement in the management of Human Immunodeficiency Virus (HIV) infection [1.9.2]. Approved by the FDA in 2003, it introduced a novel class of antiretroviral drugs known as fusion inhibitors [1.2.1, 1.9.1]. Unlike other antiretrovirals that act once the virus is already inside the host cell, enfuvirtide works extracellularly to block the virus from entering in the first place [1.3.1]. This unique mechanism provides a crucial therapeutic option, especially for treatment-experienced patients who have developed resistance to other drug classes [1.4.3]. The drug is a 36-amino-acid synthetic peptide administered via subcutaneous injection, typically twice daily [1.2.1, 1.4.1]. Its development was aimed at fulfilling the unmet need for agents with activity against multidrug-resistant HIV strains [1.4.3].
The Specific Molecular Target: HIV-1 Glycoprotein 41 (gp41)
The direct answer to 'What is the target of enfuvirtide?' is the gp41 transmembrane glycoprotein subunit of the HIV-1 virus [1.8.3]. The HIV envelope is studded with glycoproteins, translated as a gp160 polyprotein, which is then cleaved into gp120 and gp41 [1.3.1]. These two components are essential for the virus to infect a human cell, typically a CD4+ T-cell.
The infection process follows a sequence of steps:
- Attachment: The gp120 protein on the surface of HIV binds to the CD4 receptor on the host cell [1.3.1].
- Co-receptor Binding: This initial binding causes a conformational change in gp120, allowing it to bind to a second host cell receptor, usually CCR5 or CXCR4 [1.3.5].
- Fusion: This secondary binding triggers a major conformational change in gp41. The gp41 protein contains two key regions known as heptad repeats, HR1 and HR2. It exposes a hydrophobic fusion peptide that inserts into the host cell's membrane. Then, the HR2 region folds back onto the HR1 region, forming a stable six-helix bundle [1.3.1, 1.3.5]. This "hairpin" structure pulls the viral and cellular membranes together, creating a pore through which the viral capsid enters the host cell's cytoplasm [1.3.5].
Detailed Mechanism of Action
Enfuvirtide is a biomimetic peptide, meaning it was rationally designed to mimic a component of the viral machinery [1.2.4]. Specifically, its amino acid sequence is homologous to a segment of the HR2 region of gp41 [1.3.5].
During the fusion process, there is a transient intermediate state where HR1 is exposed before HR2 can fold back onto it. Enfuvirtide exploits this window of opportunity [1.3.1]. It binds with high affinity to the HR1 domain on the gp41 subunit [1.3.2, 1.8.3]. By occupying this site, enfuvirtide physically blocks the HR2 region from binding to HR1. This prevents the formation of the critical six-helix bundle and the final hairpin conformational change [1.3.1, 1.3.2]. Without this final step, the viral and cellular membranes cannot fuse, the viral core cannot enter the cell, and viral replication is effectively halted [1.2.3].
Clinical Role and Administration
Enfuvirtide is indicated for use in combination with other antiretroviral agents for treatment-experienced adults and children with ongoing HIV-1 replication despite current therapy [1.4.2]. It is not a first-line treatment due to its cost and the requirement for twice-daily subcutaneous injections, which can be burdensome for patients [1.2.1]. The standard adult dose is 90 mg injected twice a day into the upper arm, abdomen, or thigh [1.4.1]. Patients must be trained to reconstitute the lyophilized powder and self-administer the injection, rotating injection sites to minimize local reactions [1.4.2]. The most common side effects are injection-site reactions (ISRs), which occur in almost all patients and can include pain, redness, induration, and nodules [1.2.3, 1.6.5].
HIV Entry Inhibitor Comparison
Enfuvirtide belongs to a broader class of drugs called entry inhibitors, which target different steps of the viral entry process. While it was the first fusion inhibitor, other agents targeting entry have since been developed [1.7.4].
| Inhibitor Class | Drug Example(s) | Target | Mechanism |
|---|---|---|---|
| Fusion Inhibitor | Enfuvirtide (Fuzeon) | gp41 | Binds to gp41 HR1, preventing the conformational change needed for membrane fusion [1.3.2, 1.7.2]. |
| CCR5 Antagonist | Maraviroc (Selzentry) | CCR5 co-receptor | Binds to the host cell's CCR5 co-receptor, preventing gp120 from using it for entry [1.7.4, 1.7.5]. |
| Attachment Inhibitor | Fostemsavir | gp120 | Binds directly to the viral gp120 protein, preventing its initial attachment to the host cell's CD4 receptor [1.7.1]. |
| Post-Attachment Inhibitor | Ibalizumab | CD4 receptor | A monoclonal antibody that binds to the CD4 receptor after gp120 has already attached, blocking the conformational changes needed for entry [1.7.4]. |
Resistance and Limitations
As with all antiretrovirals, resistance to enfuvirtide can develop. This typically occurs through mutations in the gp41 protein, specifically within the HR1 domain at amino acid positions 36-45, which is the binding site for the drug [1.3.5, 1.5.3]. These mutations decrease the binding affinity of enfuvirtide, reducing its efficacy [1.5.1]. However, these resistance mutations often come at a cost to the virus, reducing its overall replicative capacity or "fitness" [1.5.2]. Another limitation is its lack of activity against HIV-2 [1.3.1]. Despite these challenges and its discontinuation in some markets, its development paved the way for targeting the HIV entry process and it remains an important conceptual tool and a salvage therapy option in certain contexts [1.4.2].
Conclusion
The target of enfuvirtide is the HR1 domain of the HIV-1 gp41 glycoprotein [1.8.3]. By interrupting the final, critical step of membrane fusion, enfuvirtide provided a novel mechanism to combat HIV, particularly in patients with extensive drug resistance. While its use is limited by its injectable formulation and the development of newer oral agents, its discovery was a landmark achievement in antiretroviral therapy, proving that the complex process of viral entry is a druggable target. For a more detailed history of its development, you can explore resources like the Nature Reviews Drug Discovery article on its approval [1.2.3].
