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Editing flagellin derivatives for exploration of potent radioprotective agents
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  • Tong Shi,
  • Jun Jiang,
  • Meng Gao,
  • Ronglin Ma,
  • Xuejun Chen,
  • Ruihua Zhang,
  • Jianfu Xu,
  • Weili Wang,
  • Shujuan Xu,
  • Xi Liu,
  • Huizhen Zheng,
  • Chen Wang,
  • Liqin Li,
  • Ruibin Li
Tong Shi
State Key Laboratory of NBC Protection for Civilian
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Jun Jiang
Soochow University
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Meng Gao
Soochow University
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Ronglin Ma
Soochow University
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Xuejun Chen
State Key Laboratory of NBC Protection for Civilian
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Ruihua Zhang
State Key Laboratory of NBC Protection for Civilian
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Jianfu Xu
State Key Laboratory of NBC Protection for Civilian
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Weili Wang
Soochow University
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Shujuan Xu
Soochow University
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Xi Liu
Soochow University
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Huizhen Zheng
Soochow University
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Chen Wang
State Key Laboratory of NBC Protection for Civilian
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Liqin Li
State Key Laboratory of NBC Protection for Civilian
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Ruibin Li
Soochow University

Corresponding Author:[email protected]

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Abstract

Exploration of medical radiation countermeasures (MRCs) has great implications in protection of mammals from radiation damages. While flagellin has been recently reported to show radioprotective effects, the relationships between flagellin structure and radioprotective activity are rarely explored. Herein, we deliberately edited the amino acid sequence of flagellin in its binding domain with toll-like receptor 5 (TLR5) for exploration of potent flagellin derivatives (Fds). An in vitro screening paradigm was developed to examine the radioprotective effects of six engineered Fds. Notably, mutation of 103 threonine on flagellin into asparagine resulted in a potent MRC candidate (Fd-T103N) displaying 1.28-fold increment of interactions with TLR5. Fd-T103N was able to further activate NF-κB pathway, induce immune protective cytokine (e.g. G-CSF) release, and significantly ameliorate γ-irradiation induced cell death. The protection effects of Fd-T103N were further validated in mice exposed to 10 Gray γ-irradiations. Compared to parent flagellin, Fd-T103N treatment showed higher G-CSF release in mouse blood, lower intestine damages, and 13% increments of mouse survival rates. In short, the established predictive paradigm could greatly reduce the labor-, time- and animal-costs in exploration of MRC candidates. Fd-T103N is a promising candidate of investigational new drug for radioprotection.