Design and characterization of defined alpha-helix mini-proteins with intrinsic cell permeability.

Autor: Chen XC; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China., Kong XW; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China; Department of Otorhinolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: kongxw8@mail.sysu.edu.cn., Chen P; National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou 510006, P. R. China., Li ZQ; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China., Huang N; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China., Zhao Z; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China., Yang J; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China., Zhao GX; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China., Mo Q; National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou 510006, P. R. China., Lu YT; National Supercomputer Center in Guangzhou, School of Computer Science and Engineering, Sun Yat-Sen University, Guangzhou 510006, P. R. China., Huang XM; Department of Otorhinolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China., Feng GK; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China. Electronic address: fengguok@sysucc.org.cn., Zeng MS; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P. R. China. Electronic address: zengmsh@sysucc.org.cn.
Jazyk: angličtina
Zdroj: Computational biology and chemistry [Comput Biol Chem] 2024 Dec; Vol. 113, pp. 108271. Date of Electronic Publication: 2024 Oct 31.
DOI: 10.1016/j.compbiolchem.2024.108271
Abstrakt: Proteins with intrinsic cell permeability that can access intracellular targets represent a promising strategy for novel drug development; however, a general design principle is still lacking. Here, we established a library of 46,678 de novo-designed mini-proteins and performed cell permeability screening via phage display. Analyses revealed a characteristic neighboring distribution of positive charges across helices among enriched mini-proteins of CPP7, CPP11, CPP55, CPP109 and CPP112. Compared with the state-of-the-art cell-penetrating mini-protein ZF5.3, the optimized mini-protein CPP11D36R exhibited a sevenfold increase in cell permeability. Endocytosis uptake and early endosome release are the key penetrating mechanisms. A machine learning model with high-throughput data achieved an F1 score of 0.41, significantly outperforming the previously reported CPP prediction models, including MLACP, CPPpred and CellPPD, by 41 %. Overall, our findings validate the effectiveness of a helical structure with a cationic distribution as a design principle on a large scale and present a robust approach for the development of cell-permeable mini-protein drugs.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mu-Sheng Zeng, Xin-Chun Chen, Xiang-Wei Kong and Guo-Kai Feng have filed a patent application (Patent application No. 2024113133880) related to the work described in this manuscript. The authors have no other conflicts of interest to declare.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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