Journal Article

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

Huang, Gongchao, Zhang, Junling, Zhang, Qianru, Tian, Hongqi, Li, Kui, Zhu, Zhimei

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/31 / 13/51 / 38/47 / 631/154/1435 / 64/60 / 692/308/153 / 82/80 / Amifostine / Amifostine - pharmacology / Animals / Antibodies / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Culture / Cell Line / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA - metabolism / Enantiomers / Ferroptosis / Ferroptosis - drug effects / Ferroptosis - radiation effects / Glutathione - metabolism / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - metabolism / Hematopoietic Stem Cells - pathology / Hematopoietic Stem Cells - radiation effects / Immunology / Intestinal Mucosa - drug effects / Intestinal Mucosa - metabolism / Intestinal Mucosa - pathology / Intestinal Mucosa - radiation effects / Ionizing radiation / Jejunum - drug effects / Jejunum - metabolism / Jejunum - pathology / Jejunum - radiation effects / Life Sciences / Lipid Peroxidation - drug effects / Lung - drug effects / Lung - metabolism / Lung - pathology / Lung - radiation effects / Male / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Nude / Oxidative Stress - drug effects / Peptides / Peptides - chemical synthesis / Peptides - metabolism / Peptides - pharmacology / Radiation Dosage / Radiation Injuries - genetics / Radiation Injuries - metabolism / Radiation Injuries - pathology / Radiation Injuries - prevention & control / Radiation-Protective Agents - chemical synthesis / Radiation-Protective Agents - metabolism / Radiation-Protective Agents - pharmacology / Rats / Toxicity / Whole-Body Irradiation