Anti-radiation Drug Screening From Structural Anologue Of Lipopeptide H6101and Mechanism Research

Radioprotectors are needed to protect cancer patient with radiotherapy and otherpotentially exposed populations, such as workers in the nuclear-power industry, spacetravellers or operators on radio active devices. Great efforts are put into searching forideal radioprotectors considering its importance. H6101, also known as CBLB612, isa lipopeptide as a new anti-radiation drug which is being researched and developed byCleveland Biolabs company in USA. H6101showed a significant protective effect onthe survival of irradiated mice. The compound is a fatty acid or other lipophilicmolecules connected with the peptide compounds by a covalent bond. It binds toTLR2and TLR6dimer on the cell membrane, activates downstream signalingpathways, inhibits of radiation-induced apoptosis and tissue damage, enhances thebody to radiation resistance. H6101is a very promising new radiation protection drug.A cell model and a mouse model is built to screen the compound from H6101structural analogue having the activity of anti-radiation. We observed the protectiveeffect on mouse bone marrow cells and macrophages after irradiation and explored itsmechanism from the gene level, the molecular level, cellular level. The followingpreliminary conclusions are drawed:1. Some of the compounds was insoluble in water. We screened the different typeand ratio of fat-soluble solvent from pharmaceutical excipients. So the formulation thefat-soluble compounds initially identified is ethanol: propylene glycol: dimethylethanolamine=1:4:5; We screened anti-radiation activity of66H6101lipopeptidestructural analogues through the model of30-day survival of irradiated mice andfound that anti-radiation activity of14compounds were better than H6101at aadministration dose of150μg/kg,450μg/kg. Anti-radiation activity of LK-SF307wasbetter than H6101at both administration dose of150μg/kg,450μg/kg. We also foundthat the anti-radiation activity of LK-SF307was better than H6101at differentadministration time before or after irradiation, different administrattion dose, differentdose of irradiation;2. Micro-array and protein chip technology were applied to analysis the changeof gene expression profiles and cytokine. We found that H6101is able to activateNF-κB signaling pathway as well as inhibit of apoptosis, promote hematopoietic andother functions. The role of cytokines chip may also reflect the H6101can promotethe expression of granulocyte colony-stimulating factor, interleukin-6and othercytokines;3. Immunofluorescence proved H6101could promote nuclear translocation ofNF-kappa B subunit p65.This shows that H6101could activated internal endogenousNF-kappaB signaling pathway. H6101could also inhibit the irradiation-inducedapoptosis, which play the role of anti-radiation.