Skip to content
1887

Abstract

In , phosphoproteins (P) are essential polymerase cofactors, forming oligomers and interacting with viral components to facilitate replication. Previous studies have demonstrated that a P-derived peptide (PFr) from the respiratory syncytial virus (RSV), containing the oligomerization domain (OD) and C-terminal domain (CTD), effectively inhibits RSV replication. Here, we extend this approach to paramyxoviruses, including HPIV3, MeV and MuV. Customized PFrs exhibited potent inhibitory effects against their respective viruses, with IC values below 100 nM, while showing minimal cytotoxicity. These findings highlight the potential of targeting P oligomerization as a broad-spectrum antiviral strategy for paramyxoviruses and other mononegaviruses.

Funding
This study was supported by the:
  • Taiho Pharmaceutical
    • Principal Award Recipient: HaraKoyu
  • Daiichi-Sankyo
    • Principal Award Recipient: HaraKoyu
  • Asahi Kasei Pharma Corporation
    • Principal Award Recipient: HaraKoyu
  • Shionogi
    • Principal Award Recipient: HaraKoyu
  • KAKENHI (Award 21K07763)
    • Principal Award Recipient: HaraKoyu
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.002062
2024-12-17
2025-12-17

Metrics

Loading full text...

Full text loading...

References

  1. Amarasinghe GK, Ayllón MA, Bào Y, Basler CF, Bavari S et al. Taxonomy of the order Mononegavirales: update 2019. Arch Virol 2019; 164:1967–1980 [View Article] [PubMed]
    [Google Scholar]
  2. Cardone C, Caseau CM, Pereira N, Sizun C. Pneumoviral phosphoprotein, a multidomain adaptor-like protein of apparent low structural complexity and high conformational versatility. Int J Mol Sci 2021; 22:1537 [View Article] [PubMed]
    [Google Scholar]
  3. Liang B. Structures of the Mononegavirales polymerases. J Virol 2020; 94:
    [Google Scholar]
  4. Bloyet LM. The nucleocapsid of paramyxoviruses: structure and function of an encapsidated template. Viruses 2021; 13:2465 [View Article] [PubMed]
    [Google Scholar]
  5. Ding H, Green TJ, Lu S, Luo M. Crystal structure of the oligomerization domain of the phosphoprotein of vesicular stomatitis virus. J Virol 2006; 80:2808–2814 [View Article] [PubMed]
    [Google Scholar]
  6. Bruhn JF, Barnett KC, Bibby J, Thomas JMH, Keegan RM et al. Crystal structure of the Nipah virus phosphoprotein tetramerization domain. J Virol 2014; 88:758–762 [View Article] [PubMed]
    [Google Scholar]
  7. Communie G, Crépin T, Maurin D, Jensen MR, Blackledge M et al. Structure of the tetramerization domain of measles virus phosphoprotein. J Virol 2013; 87:7166–7169 [View Article] [PubMed]
    [Google Scholar]
  8. Cox R, Green TJ, Purushotham S, Deivanayagam C, Bedwell GJ et al. Structural and functional characterization of the mumps virus phosphoprotein. J Virol 2013; 87:7558–7568 [View Article] [PubMed]
    [Google Scholar]
  9. Tarbouriech N, Curran J, Ruigrok RW, Burmeister WP. Tetrameric coiled coil domain of sendai virus phosphoprotein. Nat Struct Biol 2000; 7:777–781 [View Article] [PubMed]
    [Google Scholar]
  10. Gilman MSA, Liu C, Fung A, Behera I, Jordan P et al. Structure of the respiratory syncytial virus polymerase complex. Cell 2019; 179:193–204 [View Article] [PubMed]
    [Google Scholar]
  11. Leyrat C, Renner M, Harlos K, Grimes JM. Solution and crystallographic structures of the central region of the phosphoprotein from human metapneumovirus. PLoS One 2013; 8:e80371 [View Article] [PubMed]
    [Google Scholar]
  12. Bruhn JF, Kirchdoerfer RN, Urata SM, Li S, Tickle IJ et al. Crystal structure of the Marburg virus VP35 oligomerization domain. J Virol 2017; 91:e01085-16 [View Article] [PubMed]
    [Google Scholar]
  13. Morin B, Kranzusch PJ, Rahmeh AA, Whelan SPJ. The polymerase of negative-stranded RNA viruses. Curr Opin Virol 2013; 3:103–110 [View Article] [PubMed]
    [Google Scholar]
  14. Galloux M, Gabiane G, Sourimant J, Richard C-A, England P et al. Identification and characterization of the binding site of the respiratory syncytial virus phosphoprotein to RNA-free nucleoprotein. J Virol 2015; 89:3484–3496 [View Article] [PubMed]
    [Google Scholar]
  15. Hara K, Yaita K, Khamrin P, Kumthip K, Kashiwagi T et al. A small fragmented P protein of respiratory syncytial virus inhibits virus infection by targeting P protein. J Gen Virol 2020; 101:21–32 [View Article] [PubMed]
    [Google Scholar]
  16. Yu Q, Hardy RW, Wertz GW. Functional cDNA clones of the human respiratory syncytial (RS) virus N, P, and L proteins support replication of RS virus genomic RNA analogs and define minimal trans-acting requirements for RNA replication. J Virol 1995; 69:2412–2419 [View Article] [PubMed]
    [Google Scholar]
  17. Deng T, Sharps J, Fodor E, Brownlee GG. In vitro assembly of PB2 with A PB1-PA dimer supports a new model of assembly of influenza a virus polymerase subunits into a functional trimeric complex. J Virol 2005; 79:8669–8674 [View Article] [PubMed]
    [Google Scholar]
  18. Chapman J, Abbott E, Alber DG, Baxter RC, Bithell SK et al. RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrob Agents Chemother 2007; 51:3346–3353 [View Article] [PubMed]
    [Google Scholar]
  19. Vendeville S, Tahri A, Hu L, Demin S, Cooymans L et al. Discovery of 3-({5-Chloro-1-[3-(methylsulfonyl)propyl]-1H-indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (JNJ-53718678), a potent and orally bioavailable fusion inhibitor of respiratory syncytial virus. J Med Chem 2020; 63:8046–8058 [View Article] [PubMed]
    [Google Scholar]
  20. Rhodin MHJ, McAllister NV, Castillo J, Noton SL, Fearns R et al. EDP-938, a novel nucleoprotein inhibitor of respiratory syncytial virus, demonstrates potent antiviral activities in vitro and in a non-human primate model. PLoS Pathog 2021; 17:e1009428 [View Article] [PubMed]
    [Google Scholar]
  21. Xie J, Ouizougun-Oubari M, Wang L, Zhai G, Wu D et al. Structural basis for dimerization of a paramyxovirus polymerase complex. Nat Commun 2024; 15:3163 [View Article]
    [Google Scholar]
  22. Noton SL, Deflubé LR, Tremaglio CZ, Fearns R. The respiratory syncytial virus polymerase has multiple RNA synthesis activities at the promoter. PLoS Pathog 2012; 8:e1002980 [View Article] [PubMed]
    [Google Scholar]
  23. Oliveira AP, Simabuco FM, Tamura RE, Guerrero MC, Ribeiro PGG et al. Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells. Virus Res 2013; 177:108–112 [View Article] [PubMed]
    [Google Scholar]
  24. Wan Q, Song D, Li H, He ML. Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development. Signal Transduct Target Ther 2020; 5:125 [View Article] [PubMed]
    [Google Scholar]
  25. Castel G, Chtéoui M, Caignard G, Préhaud C, Méhouas S et al. Peptides that mimic the amino-terminal end of the rabies virus phosphoprotein have antiviral activity. J Virol 2009; 83:10808–10820 [View Article] [PubMed]
    [Google Scholar]
  26. Yabukarski F, Lawrence P, Tarbouriech N, Bourhis J-M, Delaforge E et al. Structure of Nipah virus unassembled nucleoprotein in complex with its viral chaperone. Nat Struct Mol Biol 2014; 21:754–759 [View Article] [PubMed]
    [Google Scholar]
  27. Cardone C, Caseau C-M, Bardiaux B, Thureaux A, Galloux M et al. A structural and dynamic analysis of the partially disordered polymerase-binding domain in RSV phosphoprotein. Biomolecules 2021; 11:1225 [View Article] [PubMed]
    [Google Scholar]
  28. Decool H, Gonnin L, Gutsche I, Sizun C, Eléouët J-F et al. Interactions between the nucleoprotein and the phosphoprotein of pneumoviruses: structural insight for rational design of antivirals. Viruses 2021; 13:2449 [View Article] [PubMed]
    [Google Scholar]
  29. Li T, Liu M, Gu Z, Su X, Liu Y et al. Structures of the mumps virus polymerase complex via cryo-electron microscopy. Nat Commun 2024; 15:4189 [View Article]
    [Google Scholar]
  30. Guseva S, Milles S, Blackledge M, Ruigrok RWH. The nucleoprotein and phosphoprotein of measles virus. Front Microbiol 2019; 10:1832 [View Article] [PubMed]
    [Google Scholar]
  31. Kingston RL, Baase WA, Gay LS. Characterization of nucleocapsid binding by the measles virus and mumps virus phosphoproteins. J Virol 2004; 78:8630–8640 [View Article] [PubMed]
    [Google Scholar]
/content/journal/jgv/10.1099/jgv.0.002062
Loading
/content/journal/jgv/10.1099/jgv.0.002062
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An error occurred
Approval was partially successful, following selected items could not be processed due to error