Integrated Chemical Biology Approach to Study Roles of Metals in Biology and to Discover New Covalent Drug Lead Compounds

Abstract

Chemical biology is an interdisciplinary research area, applying chemical tools and technologies to study and/or manipulate biological systems. Two of the key technologies are molecular imaging and chemoproteomics, which enable us to real-time monitor biological events and profile protein targets with specific functions respectively. Fluorescent probes are known to be important tools for molecular imaging of biomolecules/ions. Recent advances in the field include the development of new generation of probes for achieving good quantification and spatial resolution of biomolecules/ions. In this talk, I will illustrate this using my previous work on ratiometric FRET Cu(I) probe1 and Cu(I)-directed acyl imidazole probe,2 which allows internal self-calibration for better quantification and labeling of Cu(I) hotspots for preserving the spatial information of Cu(I) ion respectively. These are important for understanding changes in labile Cu(I) pools in cells under oncogenic transformations and the different Cu homeostasis in different brain cells. Chemoproteomics has demonstrated great impact in drug research and discovery. By coupling with gel-based experiments and high resolution mass spectrometry (MS), new druggable hotspots and covalent drugs with defined protein targets and binding sites can be identified. I will use my previous work on EN6, a cysteine-reactive compound which can activate autophagy and inhibit mTORC1 signaling through covalent binding of Cys277 on ATP6V1A,3 and ongoing cancer research of my lab as examples to showcase the potential of chemoproteomics in studying metals in biology and medicine. References: Chung, C. Y.-S.,† Posimo, J. M.,† Lee, S.,† Tsang, T.,† Davis, J. M., Brady, D. C., & Chang, C. J. Proceedings of the National Academy of Sciences 2019, 116(37), 18285-18294. Lee, S.,† Chung, C. Y.,† Liu, P., Craciun, L., Nishikawa, Y., Bruemmer, K. J., Hamachi, I., Saijo, K., Miller, E. W., & Chang, C. J. Journal of the American Chemical Society 2020, 142(35), 14993–15003. Chung, C. Y.-S.,† Shin, H. R.,† Berdan, C. A., Ford, B., Ward, C. C., Olzmann, J. A., Zoncu, R., & Nomura, D. K. Nature Chemical Biology 2019, 15(8), 776–785.