Effective Radioprotectants Targeting Toll-like Receptor 5

DESCRIPTION (provided by applicant): Protection of the human organism from ionizing radiation (IR) is a key problem in radiation therapy, nuclear safety and space travel. At the organismal level, the resistance to IR is limited by radiosensitivity of the cells in a few vitally important tissues, such as the hematopoietic and lymphoid systems and the epithelium of the gastrointestinal tract, which undergo massive apoptotic death leading to organ failure and reduction of regenerating capacity. We have previously shown that a radioprotective effect can be reached by modulation of two apoptosis-regulating signaling pathways, p53 and NF-?B, thus validating apoptosis modulators as prospective radioprotectants. Furthermore, we have demonstrated that NF-kappaB activating factor, flagellin of Salmonella, that act by activation of Toll-like receptor 5 (TLR5), provides powerful radioprotection of mice from both hematopoietic and gastrointestinal radiation syndromes. The radioprotection effect of flagellin has been linked to its TLR5-interacting NF-kappaB activating region. This discovery defines the major goal of this project as development of effective and safe radioprotectants acting through activation of TLR5. This goal can be achieved through (i) optimization of existing natural TLR5 activator flagellin to reduce protein size and immunogenicity, and (ii) screening of small molecules which, like flagellin, are capable of activating TLR5. Since the existing level of knowledge does not allow choosing between these two paths, we propose to conduct additional relatively small-scale exploratory studies to determine: (i) to what extend the size of flagellin can be reduced without loosing its radioprotective efficacy and (ii) whether isolation of small molecules activating TLR5 is feasible. In the end of the Phase I of the study, the company will be in a position to decide which direction will be taken to Phase II, which will be focused on further optimization of selected candidates and bringing them forward towards comprehensive preclinical characterization as prospective radioprotectors.