摘要：一项近日发表在Cell的工作主要通过机器学习[1]–[6]辅助的定向进化开发新平台，实现了动物体内可控的蛋白激活或者互作，从而帮助人们进一步研究生理病理机制，以及开发更“可控”的药物[7]。

https://www.cell.com/cell/abstract/S0092-8674(25)00517-3

一项近日发表在Cell的工作主要通过机器学习[1]–[6]辅助的定向进化开发新平台，实现了动物体内可控的蛋白激活或者互作，从而帮助人们进一步研究生理病理机制，以及开发更“可控”的药物[7]。

该方法的关键是定向进化非天然氨基酸编码系统[8]–[11]，并结合小分子诱导的非天然氨基酸“de-caging”[12]，在动物体内实现可控的蛋白“gain-of-Function”[7]。

研究人员使用该方法在小鼠体内肿瘤细胞特异地触发了细胞焦亡（pyroptosis），以及操纵免疫细胞和肿瘤细胞的互作；并进一步通过引入更多的非天然氨基酸展示该方法潜在的通用性[7]。

该项工作的通讯作者是北京大学的陈鹏和王初等研究人员；2025年5月27日在线发表在Cell[7]。

Comment(s):

将来原位引入动物体内有望进一步研究发育、再生乃至神经生物学等领域的科学问题。

如何实现多通道（同时操纵多种蛋白）？可逆？以及进一步的效率？等等是需要后续研究的问题。

参考文献：

[1] J. Jumper et al., “Highly accurate protein structure prediction with AlphaFold,” Nature, vol. 596, no. 7873, pp. 583–589, 2021, doi: 10.1038/s41586-021-03819-2.

[2] A. Rives et al., “Biological structure and function emerge from scaling unsupervised learning to 250 million protein sequences.,” Proc. Natl. Acad. Sci. U. S. A., vol. 118, no. 15, Apr. 2021, doi: 10.1073/pnas.2016239118.

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[6] R. F. Alford et al., “The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design.,” J. Chem. Theory Comput., vol. 13, no. 6, pp. 3031–3048, Jun. 2017, doi: 10.1021/acs.jctc.7b00125.

[7] X. Wang et al., “Machine-learning-assisted universal protein activation in living mice,” Cell, May 2025, doi: 10.1016/j.cell.2025.05.006.

[8] L. Wang, A. Brock, B. Herberich, and P. G. Schultz, “Expanding the Genetic Code of Escherichia coli,”Science (80-. )., vol. 292, no. 5516, pp. 498–500, Apr. 2001, doi: 10.1126/science.1060077.

[9] J. Li et al., “Palladium-triggered deprotection chemistry for protein activation in living cells.,” Nat. Chem., vol. 6, no. 4, pp. 352–361, Apr. 2014, doi: 10.1038/nchem.1887.

[10] J. Wang et al., “Time-resolved protein activation by proximal decaging in living systems.,” Nature, vol. 569, no. 7757, pp. 509–513, May 2019, doi: 10.1038/s41586-019-1188-1.

[11] G. Zhang et al., “Bioorthogonal Chemical Activation of Kinases in Living Systems.,” ACS Cent. Sci., vol. 2, no. 5, pp. 325–331, May 2016, doi: 10.1021/acscentsci.6b00024.

[12] R. M. Versteegen, W. Ten Hoeve, R. Rossin, M. A. R. de Geus, H. M. Janssen, and M. S. Robillard, “Click-to-Release from trans-Cyclooctenes: Mechanistic Insights and Expansion of Scope from Established Carbamate to Remarkable Ether Cleavage.,” Angew. Chem. Int. Ed. Engl., vol. 57, no. 33, pp. 10494–10499, Aug. 2018, doi: 10.1002/anie.201800402.

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来源：科学新天地