Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing groupof virus-encoded transmembrane oligomeric proteins that allow passage of small molecules across the membrane.Despite sparsity in viroporin structures, recent work has revealed diversity in both the number of transmembranehelices and oligomeric states. Here, we provide evidence that the small hydrophobic protein (SH) from mumps virusis a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracel-lular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expres-sion of wild-type SH and variants in Xenopus laevis oocytes reveals the viroporin as a chloride channel, with transportfacilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by thesmall-molecule BIT225, highlighting the potential for antiviral targeting through SH
