Targeting N-terminal Cysteine Residues with Photofunctional Transition Metal Complexes for Site-specific Bioconjugation, Live-cell Imaging, and Phototherapeutic Applications
DescriptionThe aim of the project is the development of photofunctional transition metal complexes that can target N-terminal cysteine residues, and the exploitation of the luminescence properties and photocytotoxic activity of these complexes for diagnostic and therapeutic applications. Chemical modification of peptides and proteins has resulted in the creation of new molecular tools for biological and biomedical applications. However, traditional bioconjugation methods often lead to heterogeneous labeling due to a lack of regioselectivity, rendering characterization of the conjugates and control of their properties a daunting task. Thus, significant effort hasbeen devoted to the development of chemoselective reactions that enable peptide and protein modification in a site-specific manner. In recent years, biocompatible reactions that offer single-site modification at the N-terminal cysteine over other amino acids including internal and C-terminal cysteines have received considerable attention. The interest stems from the low natural abundance of proteins with an N-terminal cysteine and the fact that the modification of this residue has minimal interference with the structures and functions of peptides and proteins. In the past decade, there has been enormous interest in the design of luminescent transition metal complexes for sensing, bio-imaging, and phototherapeutic applications due to their favorable photophysical properties and singlet oxygen (1O2)-photosensitization behavior. We envisage that combining the luminescence and photochemical properties of metal complexes with specific N-terminal cysteine modification will afford innovative biological reagents for diagnostic and therapeutic applications. In this project, we will functionalize transition metal complexes with a 1,2-aminothiol-sensitive moiety, which is able to modulate the luminescence and 1O2-photosensitization properties of the complexes at the same time. In our designs,bioconjugation of the complexes to peptides and proteins with an N-terminal cysteine will not only turn on the emission of the complexes, but also activate their 1O2-photosensitization capability, which cannot be readily achieved using the existing organic-based bioconjugation reagents. These specially designed complexes will allow phosphorogenic labeling of proteins in live cells, examination of protein dynamics, and construction of novel photocytotoxic bioconjugates. We are confident that the exploration of photofunctional transition metal complexes that possess specific N-terminal cysteine reactivity will afford novel bioconjugateswith diverse and enriched functionalities. Results generated from the project will further emphasize the unique features of photofunctional transition metal complexes, which will offer new insights into biomolecular interactions, cellular events, and enzyme functions. Ultimately, these innovative bioconjugation reagents will provide unprecedented opportunities for medicine and materials related to diagnosis and therapy.
|Effective start/end date||1/01/23 → …|