Inorganic Chemistry Tools for Bioconjugation, Recognition and Imaging

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Project Summary/Abstract Our laboratory is interested in developing new inorganic chemistry tools to address unmet needs in the areas of bioconjugation, recognition, and imaging. In order to tackle these challenges, new molecular scaffolds and biocompatible chemistry are crucial. The overall objective of this MIRA application is to further advance the field of organomimetic boron cluster chemistry. Organomimetic features of these clusters arise from 1) their ability to undergo facile functionalization chemistry with a wide array of substituents, forming stable covalent bonds attached to the cluster¢s vertices and 2) unique 3D aromaticity, rendering these clusters amenable for several modes of microscopy imaging. Within the scope of this work is also a set of new, rapid organometallic transformations that were discovered during the original cycle of the MIRA funding that would allow one to rationally tether boron clusters and other molecules under biologically relevant conditions. Our laboratory is interested in developing new transformations that mimic the operational simplicity with which thiol ligands normally assemble onto a metallic gold surface. This chemistry has previously revolutionized the ease with which we can create hybrid noble metal nanoparticles (e.g., thiol capped gold nanoparticles - AuNPs). However, these hybrid AuNPs are not atomically precise, and the ligand corona is dynamic. These features lead to hybrids with a non-uniform composition and size, ultimately limiting their applications for the inhibition of protein-biomolecule interactions. Addressing this challenge, we have developed organometallic- based methods for cluster modification, providing a covalently tethered dense corona of functional biomolecules and ligands spatially arranged with three-dimensional precision. We propose to further expand this approach to rapidly build up sophisticated atomically-precise 3D nanomolecules for multivalent binding to various biological targets, including virus entry receptors, biological membranes, and cellular growth factors. We also propose to utilize the inherent robustness and reaction kinetics associated with the developed Au-based reagents for biomolecular positron-emission tomography (PET) labeling. We have also been engaged in the development of new boron cluster chemistry, allowing for the positioning of multiple reactive functional groups on a three- dimensional cluster and use these rigid 3D species to label and tether biomolecules to achieve unconventional folding and recognition. We propose chemistry that will enable the labeling of small molecules, peptides, proteins, and cells with various boron cluster scaffolds, which can subsequently be used as multivalent binders, affinity tags, and fluorescent-free labels using Raman microscopy imaging. Lastly, we propose the use of perfunctionalized boron clusters as dual staining/fluorophore agents for correlative light and electron microscopy (CLEM). Specifically, we will work on developing hybrids that contain heavy atom perfunctionalized boron cluster stains tethered to a fluorescent dye, which would enable targeting of specific cellular organelles, thereby providing access to an unprecedented class of photostable and non-toxic agents for CLEM.