Enfuvirtide

Enfuvirtide is a synthetic 36-amino acid peptide that inhibits HIV-1 entry into host cells by binding to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational change required for fusion of the viral and cellular membranes. This blocks viral entry after CD4 receptor and coreceptor (CCR5/CXCR4) binding but before genetic material is inserted into the host cell. Because it is a peptide, it must be administered via subcutaneous injection (not orally bioavailable due to degradation by gastrointestinal enzymes), typically twice daily. It is primarily used in combination antiretroviral therapy for treatment-experienced patients with multidrug-resistant HIV strains who have limited other options, rather than as first-line therapy due to cost, administration route, and side effect profile. The most common adverse effect is local injection site reactions (pain, erythema, induration, nodules), occurring in the majority of patients. Other effects include increased risk of bacterial pneumonia and hypersensitivity reactions. Resistance can develop through mutations in the gp41 HR1 region. Enfuvirtide represented the first approved entry inhibitor and a novel drug class, distinguishing it mechanistically from reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors used more commonly as first-line agents.