Abstract
Amifostine has been the only small molecule radio-protector approved by FDA for decades; however, the serious adverse effects limit its clinical use. To address the toxicity issues and maintain the good potency, a series of modified small polycysteine peptides had been prepared. Among them, compound 5 exhibited the highest radio-protective efficacy, the same as amifostine, but much better safety profile. To confirm the correlation between the radiation-protective efficacy and the DNA binding capability, each of the enantiomers of the polycysteine peptides had been prepared. As a result, the l-configuration compounds had obviously higher efficacy than the corresponding d-configuration enantiomers; among them, compound 5 showed the highest DNA binding capability and radiation-protective efficacy. To our knowledge, this is the first study that has proved their correlations using direct comparison. Further exploration of the mechanism revealed that the ionizing radiation (IR) triggered ferroptosis inhibition by compound 5 could be one of the pathways for the protection effect, which was different from amifostine. In summary, the preliminary result showed that compound 5, a polycysteine as a new type of radio-protector, had been developed with good efficacy and safety profile. Further study of the compound for potential use is ongoing.
Highlights
Total body irradiation (TBI) may induce injury in many tissues and organs
There are three important concepts were systematically considered in our compound designing: firstly, the polycysteine peptide backbone to alleviate the toxicity possibly caused from the polyamine, which is the amifostine structure backbone; secondly, the number of terminal thiol segments in the amide side chain backbone is increased to elevate reactive oxygen species (ROS) scavenging ability; thirdly, the perpendicular, alkyl sidechain with a terminal thiol projected away from the DNA backbone to enable ROS scavenging around DNA, the same idea as Prc-210
We executed the 30-day survival experiment, as shown in Fig. 1b, c; when mice were exposed to 7.2 Gy TBI, the survival rate is 0%; 80% mice survived in compound 5 and amifostine-treated mice groups, followed by 70% in compound 3, 40% in compound 6, 30% in compound 4, 20% in compound 9 and compound 1, 10% in compound 8, compound 2, and L-cysteine-treated mice groups
Summary
Total body irradiation (TBI) may induce injury in many tissues and organs. Direct action destroys cellular molecular structure, leading to abnormal function and metabolic disorders. It has been reported that many kinds of anti-oxidative compounds have radiation protective effect[4,5,6]. Few of these compounds have clear efficacy and superior performance. Thiol in amifostine and other aminothiol radiation protectors had been considered as the functional chemical group which can scavenge free radicals and protect against radiation-induced injury effectively. It seems that number of thiols in the compound is not the only factor to evaluate the radio-protective efficacy. The molecular weight of N-acetyl-cysteine (NAC) is less than that of amifostine, there should be more thiols when irradiated mice were treated with NAC at the same dose as amifostine; NAC is much less effective on protecting radiation-induced injury[7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
