Development of Anti-Trx-1 agents for the treatment of cancer using chemical protein synthesis

Oxidative stress and hypoxia are common states occurred in cancer microenvironment. As a consequence, tumour cells are usually associated with elevated levels of antioxidant systems, especially the thioredoxin system[1]. Thioredoxin system composed of thioredoxin reductase (TrxR), NADPH and the protein thioredoxin (Trx).This system plays a major role in many cellular functions, including maintaining cellular redox homeostasis, control of transcriptional factors, DNA synthesis, stimulating cell growth and inhibiting apoptosis[2].Trx-1, a small protein composed of 105 amino acids, is a member of the dithiol–disulfide oxidoreductase family[3] was found to be overexpressed in many solid tumour cancer cells, making it an attractive target for cancer treatments.

In this research, we will develop an inhibitor against Trx-1, which can be used as a new drug candidate against cancer with fewer side effects. The proposed inhibitor and the target (Trx-1) will be developed by chemical protein synthesis using two techniques: solid phase peptide synthesis (SPPS) and native chemical ligation (NCL).

1. Powis, G., D. Mustacich, and A. Coon, The role of the redox protein thioredoxin in cell growth and cancer. Free Radical Biology and Medicine, 2000. 29(3-4): p. 312-322.
2. Arnér, E.S. and A. Holmgren, Physiological functions of thioredoxin and thioredoxin reductase. European Journal of Biochemistry, 2000. 267(20): p. 6102-6109.
3. Holmgren, A., Thioredoxin. Annual review of biochemistry, 1985. 54(1): p. 237-271.