Structures of New World mammarenavirus glycoproteins as targets for antibody-mediated neutralization

New World mammarenaviruses (NWMs) are viral pathogens endemic to the Americas, where several have acquired the capability for zoonotic transmission, leading to sporadic but potentially lethal viral hemorrhagic fever in humans. Several NWMs are classified as category A pathogens and are considered a persistent threat to human health due to their high case mortality rates, ability to spread through airborne transmission, and limited therapeutic and treatment options against them. Infection is mediated by the tripartite glycoprotein complex (GPC), which is the sole protein expressed on the viral envelope. The GPC, consisting of a receptor-binding domain (GP1), a fusion-enabling domain (GP2), and a stable signal peptide (SSP), governs viral entry initiated through the transferrin receptor 1 (TfR1). Subtle changes in GPC sequence and structure can drastically influence host range, immune recognition, and viral fitness, underscoring its central role in arenavirus pathogenicity and making it a prime target for therapeutic intervention. Over the past decade, advances in structural biology have enabled the elucidation of the molecular architecture of the NWM GPC and its interaction with host receptors and neutralizing antibodies. In this review, we discuss the information gleaned from structural interrogation of the NWM GPC and the significance of these findings on current therapeutic development against these lethal pathogens.