Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development

The peptidic antiretroviral enfuvirtide (Fuzeon) is the first clinically approved antiviral fusion inhibitor and the first antiretroviral that must routinely be administered parenterally. Its extracellular activity results both in activity against current drug-resistant strains of HIV-1 and a low potential for systemic toxicities. As a peptide, enfuvirtide also exhibits few interactions with other antiretrovirals and concomitant medications used in HIV disease. Enfuvirtide shows potent antiretroviral activity and significantly improves medical outcomes in highly treatment-experienced patients with HIV-1 infection, but like other antiretrovirals must be given as part of a carefully selected combination regimen to minimise the risk of emergent drug resistance. Despite its subcutaneous route of administration, clinical data indicate that most patients can accept long-term enfuvirtide treatment with little difficulty or impact on daily activities. The only common adverse event associated with enfuvirtide use is injection-site reactions of generally mild-to-moderate severity, which are seldom treatment-limiting.