Rational Design of Phytovirucide Inhibiting Nucleocapsid Protein Aggregation in Tomato Spotted Wilt Virus

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Feb 27

PMID 40016246

Authors

Ningning Zan

Jiao Li

Jiahui Yao

Shang Wu

Jianzhuan Li

Feifei Chen

Baoan Song

Runjiang Song

Affiliations

Soon will be listed here.

Abstract

Ineffectiveness of managing plant viruses by chemicals has posed serious challenges in crop production. Recently, phase separation has shown to play a key role in viral lifecycle. Using inhibitors that can disturb biomolecular condensates formed by phase separation for virus control has been reported in medical field. However, the applicability of this promising antiviral tactic for plant protection has not been explored. Here, we report an inhibitor, Z9, that targets the tomato spotted wilt virus (TSWV) N protein. Z9 is capable of interacting with the amino acids in the nucleic acid binding region of TSWV N, disrupting the assembly of N and RNA into phase-separated condensates, the reduction of which is detrimental to the stability of the N protein. This study provides a strategy for phase separation-based plant virus control.

References

He S, Yu Y, Wang L, Zhang J, Bai Z, Li G . Linker histone H1 drives heterochromatin condensation via phase separation in Arabidopsis. Plant Cell. 2024; 36(5):1829-1843. PMC: 11062459. DOI: 10.1093/plcell/koae034. View

Shi Y, Liao Y, Liu Q, Ni Z, Zhang Z, Shi M . BRD4-targeting PROTAC as a unique tool to study biomolecular condensates. Cell Discov. 2023; 9(1):47. PMC: 10167318. DOI: 10.1038/s41421-023-00544-0. View

Ma X, Zhou Y, Moffett P . Alterations in cellular RNA decapping dynamics affect tomato spotted wilt virus cap snatching and infection in Arabidopsis. New Phytol. 2019; 224(2):789-803. DOI: 10.1111/nph.16049. View

Ding M, Xu W, Pei G, Li P . Long way up: rethink diseases in light of phase separation and phase transition. Protein Cell. 2023; 15(7):475-492. PMC: 11214837. DOI: 10.1093/procel/pwad057. View

Cui S, Song P, Wang C, Chen S, Hao B, Xu Z . The RNA binding protein EHD6 recruits the mA reader YTH07 and sequesters OsCOL4 mRNA into phase-separated ribonucleoprotein condensates to promote rice flowering. Mol Plant. 2024; 17(6):935-954. DOI: 10.1016/j.molp.2024.05.002. View

Chen Y, Liu F, Pal S, Hu Q . Proteolysis-targeting drug delivery system (ProDDS): integrating targeted protein degradation concepts into formulation design. Chem Soc Rev. 2024; 53(19):9582-9608. DOI: 10.1039/d4cs00411f. View

Saglik B, Osmaniye D, Acar Cevik U, Levent S, Kaya Cavusoglu B, Buyukemir O . Synthesis, characterization and carbonic anhydrase I and II inhibitory evaluation of new sulfonamide derivatives bearing dithiocarbamate. Eur J Med Chem. 2020; 198:112392. DOI: 10.1016/j.ejmech.2020.112392. View

Feng Z, Chen X, Bao Y, Dong J, Zhang Z, Tao X . Nucleocapsid of Tomato spotted wilt tospovirus forms mobile particles that traffic on an actin/endoplasmic reticulum network driven by myosin XI-K. New Phytol. 2013; 200(4):1212-24. DOI: 10.1111/nph.12447. View

Lin W, Nagy P . Co-opted cytosolic proteins form condensate substructures within membranous replication organelles of a positive-strand RNA virus. New Phytol. 2024; 243(5):1917-1935. DOI: 10.1111/nph.19691. View

10.

Wadsworth G, Srinivasan S, Lai L, Datta M, Gopalan V, Banerjee P . RNA-driven phase transitions in biomolecular condensates. Mol Cell. 2024; 84(19):3692-3705. PMC: 11604179. DOI: 10.1016/j.molcel.2024.09.005. View

11.

Li P, Banjade S, Cheng H, Kim S, Chen B, Guo L . Phase transitions in the assembly of multivalent signalling proteins. Nature. 2012; 483(7389):336-40. PMC: 3343696. DOI: 10.1038/nature10879. View

12.

Qin M, Geng E, Wang J, Yu M, Dong T, Li S . LATS2 condensates organize signalosomes for Hippo pathway signal transduction. Nat Chem Biol. 2024; 20(6):710-720. DOI: 10.1038/s41589-023-01516-x. View

13.

Jia W, Li W, Li Z, Li P . An all-in-one targeted protein degradation platform guided by degradation condensates-bridging bi-specific nanobodies. Cell Res. 2024; 34(5):389-392. PMC: 11061270. DOI: 10.1038/s41422-024-00942-3. View

14.

Zhao D, Xu W, Zhang X, Wang X, Ge Y, Yuan E . Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2. Protein Cell. 2021; 12(9):734-740. PMC: 7994959. DOI: 10.1007/s13238-021-00832-z. View

15.

Ambadi Thody S, Clements H, Baniasadi H, Lyon A, Sigman M, Rosen M . Small-molecule properties define partitioning into biomolecular condensates. Nat Chem. 2024; 16(11):1794-1802. PMC: 11527791. DOI: 10.1038/s41557-024-01630-w. View

16.

Wells J, Kumru K . Extracellular targeted protein degradation: an emerging modality for drug discovery. Nat Rev Drug Discov. 2023; 23(2):126-140. DOI: 10.1038/s41573-023-00833-z. View

17.

Myong S, Shorter J . Introduction: Phase Separation. Chem Rev. 2023; 123(14):8943-8944. DOI: 10.1021/acs.chemrev.3c00272. View

18.

Shinde S, Sakla A, Shankaraiah N . An insight into medicinal attributes of dithiocarbamates: Bird's eye view. Bioorg Chem. 2020; 105:104346. DOI: 10.1016/j.bioorg.2020.104346. View

19.

Roden C, Gladfelter A . RNA contributions to the form and function of biomolecular condensates. Nat Rev Mol Cell Biol. 2020; 22(3):183-195. PMC: 7785677. DOI: 10.1038/s41580-020-0264-6. View

20.

Song W, Liu L, Yu D, Bernardy H, Jirschitzka J, Huang S . Substrate-induced condensation activates plant TIR domain proteins. Nature. 2024; 627(8005):847-853. PMC: 10972746. DOI: 10.1038/s41586-024-07183-9. View