Polycysteine as a new type of radio-protector ameliorated tissue injury through inhibiting ferroptosis in mice

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.

Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy

“…Further, treatment with polycysteine derivatives limited gastrointestinal and hematopoietic toxicity as well as radiotherapy induced lung disease in murine models. Mechanistic studies showed that polycysteine diminished lipid oxidation and restored the GSH pool following radiotherapy [63]. Yet another molecule, arachidonate-15-lipoxygenase-1 (ALOX15), promotes lipid oxidation and contributes to the induction of ferroptosis [64].…”

Design, Synthesis, and Biological Evaluation of a Novel Aminothiol Compound as Potential Radioprotector

“…In addition, the thiols in the molecule are located away from the alkylamino backbone, thus eliminating ROS before they attack the DNA frame structure. Moreover, the amine and thiol groups in the molecule are capped, so its cell permeability and oral bioavailability can be increased compared with the compound previously reported by our laboratory [ 17 ]. We speculate that the capped group in the alkyl side chain of compound 12 could be cleaved by hydrolytic enzymes inside cells.…”

“…It contains a linear alkylamino backbone and three thiols which are capped at the ends of the alkyl side chains. Compared with the aminothiol compounds reported in previous studies [ 10 , 13 , 17 ], it has the following merits: (1) it contains more thiols that can exert ROS scavenging effects, (2) the thiol groups in the molecule are placed away from the alkyl backbone to enable the scavenging of ROS before they attack the DNA molecules; and (3) the amine group and the thiols in the compound are capped to increase its stability and permeability, for better absorption when administered orally. After obtaining the target compound, we investigated its radioprotective activity and mechanisms of action.…”

“…It contains a linear alkylamino backbone and three thiols which are capped at the ends of the alkyl side chains. Compared with the aminothiol compounds reported in previous studies [10,13,17], it has the following merits: (1) it contains more thiols that can exert ROS scavenging effects, (2) the thiol groups in the molecule are placed away from the alkyl backbone to enable the scavenging of ROS before they attack the DNA molecules; and…”

ROS-Responsive and pH-Sensitive Aminothiols Dual-Prodrug for Radiation Enteritis

“…Much progress has been made in the synthesis and screening of radioprotective compounds, such as aminothiols [ 10 , 11 , 12 , 13 ], polyphenols [ 14 , 15 ], and growth factors [ 16 , 17 ]. As radical scavengers, aminothiols provide H atoms to scour hydroxyl radicals or other ROS [ 18 , 19 , 20 ].…”