The SH protein of mumps virus is a druggable pentameric viroporin
Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing group of 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 transmembrane helices and oligomeric states. Here, we provide evidence that the small hydrophobic protein (SH) from mumps virus is a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracellular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expression of wild-type SH and variants in <i>Xenopus laevis</i> oocytes reveals the viroporin as a chloride channel, with transport facilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by the small-molecule BIT225, highlighting the potential for antiviral targeting through SH.
Authors
- Nanna MacAulay (ORCID: https://orcid.org/0000-0002-7800-6600)
- Birthe B. Kragelund (ORCID: https://orcid.org/0000-0002-7454-1761)
- METTE MARIE ROSENKILDE (ORCID: https://orcid.org/0000-0001-9600-3254)
- Trond Ulven (ORCID: https://orcid.org/0000-0002-8135-1755)
- Marco Giulini (ORCID: https://orcid.org/0000-0002-2691-712X)
- Asmita Manandhar (ORCID: https://orcid.org/0009-0002-4686-5459)
- Cagla Sahin (ORCID: https://orcid.org/0000-0002-2889-5200)
- Bo Hjorth Bentzen (ORCID: https://orcid.org/0000-0002-0253-4992)
- Alexandre M. J. J. Bonvin (ORCID: https://orcid.org/0000-0001-7369-1322)
- Viktoria M. S. Kjær (ORCID: https://orcid.org/0000-0002-5463-2324)
- Andreas Prestel (ORCID: https://orcid.org/0000-0002-5459-9608)
- Trine L. Toft‐Bertelsen (ORCID: https://orcid.org/0000-0001-9009-0094)
- Stavroula Louka
- Katrine Qvortrup (ORCID: https://orcid.org/0000-0003-3828-2069)
- Katja Spieß (ORCID: https://orcid.org/0000-0002-2388-4617)
- Kira Devantier (ORCID: https://orcid.org/0009-0002-4200-4707)
Institutions
- Statens Serum Institut (DK)
- University of Copenhagen (DK)
- University of Applied Sciences Utrecht (NL)
- University of Southern Denmark (DK)
- Technical University of Denmark (DK)
Publication Details
- Journal
- Science Advances
- Published
- 2025-06-06
- DOI
- https://doi.org/10.1126/sciadv.ads3071
- Citations
- 2
- Primary Topic
- Virology and Viral Diseases
- Type
- article
- Field-Weighted Citation Impact
- 2.71
Funders
- Novo Nordisk