Native functionality and therapeutic targeting of arenaviral glycoproteins

•Arenavirus entry into a host cell is orchestrated by virion-encoded glycoproteins.•Arenaviral glycoproteins form trimeric spikes and interact with host cell receptors.•Neutralizing antibodies target arenaviral glycoproteins.•Arenaviruses are vulnerable to drugs that target viral glycoprotein folding.

Surface glycoproteins direct cellular targeting, attachment, and membrane fusion of arenaviruses and are the primary target for neutralizing antibodies. Despite significant conservation of the glycoprotein architecture across the arenavirus family, there is considerable variation in the molecular recognition mechanisms used during host cell entry. We review recent progress in dissecting these infection events and describe how arenaviral glycoproteins can be targeted by small-molecule antivirals, the natural immune response, and immunoglobulin-based therapeutics. Arenaviral glycoprotein-mediated assembly and infection pathways present numerous opportunities and challenges for therapeutic intervention.