A research team, jointly led by Professor Kang Byeongheon and Professor Lee Changwook in the Department of Biological Sciences at UNIST has succeeded in identifying the mitochondria-targeted antioxidant mitoquinone (MitoQ) as a potent inhibitor of mitochondrial Hsp90, known as a tumor necrosis factor receptor-associated protein 1 (TRAP1).
Published in the Journal of the American Chemical Society (JACS), their findings have been featured on the cover of the printed edition on December 1, 2021.
In this study, the research team identified a novel druggable client binding site in TRAP1 and discovered that MitoQ is a small-molecule client mimic that binds this site. According to the research team, structural analyses also revealed an asymmetric bipartite interaction between MitoQ and the previously unrecognized drug binding sites located in the middle domain (MD) of TRAP1, which is believed to be a client binding region. Consistently, MitoQ competed effectively for the binding of client proteins to TRAP1 and displayed more potent inhibitory activity than other inhibitors targeting the ATP pocket in the N-terminal domain (NTD) of TRAP1, noted the research team.
They also noted that “The revealed molecular interaction not only makes the optimization of TRAP1-selective inhibitors feasible for improving anticancer activities but also may be applicable for the development of potent inhibitors targeting various mitochondrial heat shock protein 90 (Hsp90) family proteins to treat a range of human diseases.”
“MitoQ and its redox-crippled SB-U014/SB-U015 exhibited more potent anticancer activity in vitro and in vivo than previously reported mitochondria-targeted TRAP1 inhibitors,” said Professor Kang. “Our findings indicate that targeting the client binding site of Hsp90 family proteins offers a novel strategy for the development of potent anticancer drugs.
This research has been supported by the Basic Research Program through the Ministry of Science and ICT (MSIT) and the Tech Incubator Program for Startup (TIPS) by the Korean Ministry of SMEs and Startups (MSS).
Nam Gu Yoon, Hakbong Lee, So-Yeon Kim, et al., “Mitoquinone Inactivates Mitochondrial Chaperone TRAP1 by Blocking the Client Binding Site,” J. Am. Chem. Soc., (2021).