The invention generally provides compositions and methods of treating or preventing an arenavirus infection, using an agent that inhibits binding of an arenavirus glycoprotein 1 (GP1) polypeptide to transferrin receptor 1 (TfR1). The invention also provides methods of designing or identifying therapeutic agents that bind to or target a GP1 receptor-binding site (RBS) to inhibit arenavirus attachment to a cell, and therapeutic agents identified using the methods.