Citation: Hyoseok Kim, Changyi Cui, Kohei Toh, Genyir Ado, Tetsuya Ogawa, Yixin Zhang, Shin-ichi Sato, Yong-Beom Lim, Hiroki Kurata, Lu Zhou, Motonari Uesugi. Discovery of a self-assembling small molecule that sequesters RNA-binding proteins[J]. Chinese Chemical Letters, ;2025, 36(5): 110135. doi: 10.1016/j.cclet.2024.110135 shu

Discovery of a self-assembling small molecule that sequesters RNA-binding proteins

Hyoseok Kim ^{a, b, c, 1} ,
Changyi Cui ^{a, 1} ,
Kohei Toh ^{b, 1} ,
Genyir Ado ^b ,
Tetsuya Ogawa ^b ,
Yixin Zhang ^b ,
Shin-ichi Sato ^b ,
Yong-Beom Lim ^c ,
Hiroki Kurata ^b ,
Lu Zhou ^{a, *,} ,
Motonari Uesugi ^{a, b, d, *,}

a.
Department of Medicinal Chemistry and Fudan-Kyoto Shanghai Lab, School of Pharmacy, Fudan University, Shanghai 201203, China
b.
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
c.
Department of Materials Science and Engineering, Yonsei University, Seoul 03722, Republic of Korea
d.
Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Sakyo-ku, Kyoto 606-8302, Japan

zhoulu@fudan.edu.cn

uesugi@scl.kyoto-u.ac.jp

Received Date: 15 April 2024
Revised Date: 16 June 2024
Accepted Date: 17 June 2024
Available Online: 17 June 2024

Figures(5)

Biomolecular condensates, also known as membraneless organelles, play a crucial role in cellular organization by concentrating or sequestering biomolecules. Despite their importance, synthetically mimicking these organelles using non-peptidic small organic molecules has posed a significant challenge. The present study reports the discovery of D008, a self-assembling small molecule that sequesters a unique subset of RNA-binding proteins. Analysis and screening of a comprehensive collection of approximately 1 million compounds in the Chinese National Compound Library (Shanghai) identified 44 self-assembling small molecules in aqueous solutions. Subsequent screening of the focused library, coupled with proteome analysis, led to the discovery of D008 as a small organic molecule with the ability to condensate a specific subset of RNA-binding proteins. In vitro experiments demonstrated that the D008-induced sequestration of RNA-binding proteins impeded mRNA translation. D008 may offer a unique opportunity for studying the condensations of RNA-binding proteins and for developing an unprecedented class of small molecules that control gene expression.
- Chemical biology,
- RNA-binding proteins,
- Small molecule,
- Chemical library,
- Translation
1. [1]
  D. Hnisz, K. Shrinivas, R.A. Young, et al., Cell 169 (2017) 13–23. doi: 10.1016/j.cell.2017.02.007
2. [2]
  J.A. Ditlev, L.B. Case, M.K. Rosen, J. Mol. Biol. 430 (2018) 4666–4684. doi: 10.1016/j.jmb.2018.08.003
3. [3]
  L.B. Case, X. Zhang, J.A. Ditlev, et al., Science 363 (2019) 1093–1097. doi: 10.1126/science.aau6313
4. [4]
  C.D. Reinkemeier, G.E. Girona, E.A. Lemke, Science 363 (2019) eaaw2644. doi: 10.1126/science.aaw2644
5. [5]
  M. Heidenreich, J.M. Georgeson, E. Locatelli, et al., Nat. Chem. Biol. 16 (2020) 939–945. doi: 10.1038/s41589-020-0576-z
6. [6]
  L. Yang, R. Peltier, M. Zhang, et al., J. Am. Chem. Soc. 142 (2020) 18150–18159. doi: 10.1021/jacs.0c08463
7. [7]
  M. Yoshikawa, T. Yoshii, M. Ikuta, et al., J. Am. Chem. Soc. 143 (2021) 6434–6446. doi: 10.1021/jacs.0c12375
8. [8]
  Y. Dai, M. Farag, D. Lee, et al., Nat. Chem. Biol. 19 (2023) 518–528. doi: 10.1038/s41589-022-01252-8
9. [9]
  Z.G. Qian, S.C. Huang, X.X. Xia, Nat. Chem. Biol. 18 (2022) 1330–1340. doi: 10.1038/s41589-022-01203-3
10. [10]
  M.V. Garabedian, W. Wang, J.B. Dabdoub, et al., Nat. Chem. Biol. 17 (2021) 998–1007. doi: 10.1038/s41589-021-00840-4
11. [11]
  H. Wang, Y. Song, W. Wang, et al., J. Am. Chem. Soc. 146 (2024) 330–341. doi: 10.1021/jacs.3c09202
12. [12]
  S. Kim, J.-B. Chae, D. Kim, et al., J. Am. Chem. Soc. 145 (2023) 21991–22008. doi: 10.1021/jacs.3c06898
13. [13]
  B. Jana, S. Jin, E.M. Go, et al., J. Am. Chem. Soc. 145 (2023) 18414–18431. doi: 10.1021/jacs.3c04467
14. [14]
  S. Liu, Q. Zhang, A.N. Shy, et al., J. Am. Chem. Soc. 143 (2021) 15852–15862. doi: 10.1021/jacs.1c07923
15. [15]
  L. Hu, Y. Li, X. Lin, et al., Angew. Chem. Int. Ed. 60 (2021) 21807–21816. doi: 10.1002/anie.202103507
16. [16]
  W. Tan, Q. Zhang, J. Wang, et al., Angew. Chem. Int. Ed. 60 (2021) 12796–12801. doi: 10.1002/anie.202102601
17. [17]
  H. He, S. Liu, D. Wu, et al., Angew. Chem. Int. Ed. 59 (2020) 16445–16450. doi: 10.1002/anie.202006290
18. [18]
  Z. Feng, H. Wang, X. Chen, et al., J. Am. Chem. Soc. 139 (2017) 15377–15384. doi: 10.1021/jacs.7b07147
19. [19]
  Z. Feng, H. Wang, B. Xu, J. Am. Chem. Soc. 140 (2018) 16433–16437. doi: 10.1021/jacs.8b10542
20. [20]
  H. Wang, Z. Feng, B. Xu, J. Am. Chem. Soc. 141 (2019) 7271–7274. doi: 10.1021/jacs.9b03346
21. [21]
  M. Kato, T.W. Han, S. Xie, et al., Cell 149 (2012) 753–767. doi: 10.1016/j.cell.2012.04.017
22. [22]
  G. Ado, N. Noda, H.T. Vu, et al., Chem. Sci. 13 (2022) 5760–5766. doi: 10.1039/D1SC07151C
23. [23]
  D. Maity, M. Howarth, M.C. Vogel, et al., J. Am. Chem. Soc. 143 (2021) 3086–3093. doi: 10.1021/jacs.0c09967
24. [24]
  S. Jin, H.T. Vu, K. Hioki, et al., Angew. Chem. Int. Ed. 60 (2021) 961–969. doi: 10.1002/anie.202011604
25. [25]
  C.R. Alarcón, H. Goodarzi, H. Lee, et al., Cell 162 (2015) 1299–1308. doi: 10.1016/j.cell.2015.08.011
26. [26]
  H. Goodarzi, H.S. Najafabadi, P. Oikonomou, et al., Nature 485 (2012) 264–268. doi: 10.1038/nature11013
27. [27]
  C. Villarroya-Beltri, C. Gutiérrez-Vázquez, F. Sánchez-Cabo, et al., Nat. Commun. 4 (2013) 2980. doi: 10.1038/ncomms3980
28. [28]
  X. Wang, X. Fan, J. Zhang, et al., Cell Rep. 43 (2024) 113769. doi: 10.1016/j.celrep.2024.113769
29. [29]
  L. Wang, M. Wen, X. Cao, Science 365 (2019) eaav0758. doi: 10.1126/science.aaw7565
30. [30]
  S. Mikami, T. Kobayashi, M. Masutani, et al., Protein Expr. Purif. 62 (2008) 190–198. doi: 10.1016/j.pep.2008.09.002
31. [31]
  D.C. Dieterich, A.J. Link, J. Graumann, et al., Proc. Natl. Acad. Sci. U. S. A. 103 (2006) 9482–9487. doi: 10.1073/pnas.0601637103
32. [32]
  T.W. Han, M. Kato, S. Xie, et al., Cell 149 (2012) 768–779. doi: 10.1016/j.cell.2012.04.016
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