Toolkit for Fast, Multipurpose and Inducible Bioorthogonal Chemistry

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: JOSEPH M FOX
Organization: UNIVERSITY OF DELAWARE
Fiscal Year: 2024
Award: $493,511
Funding agency: National Institute of General Medical Sciences

Project Summary
The goal of this proposal will be to develop a diverse set of new chemical tools centered
on tetrazine ligation– the fastest known bioorthogonal reaction. This proposal describes
a continued effort to develop new bioorthogonal reagents. Methods will be developed for
the safe synthesis and direct coupling of ‘minimalist’ tetrazines to any molecule of
interest, including chemical probes and fluorescent reporters. We also propose to
develop tetrazines that can serve as “affinity bioorthogonal chemistry” tags that can
serve a dual role in enabling protein purification followed by subsequent site-selective
bioorthogonal chemistry. Applications to on-resin protein-protein and protein-biomolecule
assembly are proposed. We propose to develop efficient catalytic methods for ‘turning
on’ rapid bioorthogonal chemistry in cellular context, providing tool molecules with high
stability in the cellular environment in their ‘off’ state, and the fastest bioorthogonal
reactions to date in their ‘on’ state. Efficient photocatalysts have been developed that
can target bioorthogonal turn-on in vivo and at the subcellular level. Near-IR
photocatalysts as well as thermal catalysts will be developed as will new enabling
technologies for studying protein dynamics and for proteomic target identification.
Finally, we will also develop bioorthogonal N-acylmuramic acid (NAM) and N-
acylglucosamine (NAG) molecules for use in probe applications in microbiology and
immunology research.

Terms: <2-photon microscopy><Acids><Affinity><Bacteria><Binding><Binding Proteins><Biological><Biological Response Modifier Therapy><Biological Therapy><Biology><Biotech><Biotechnology><Boronic Acids><C-terminal><Carbohydrates><Cell Body><Cells><Chemicals><Chemistry><Closure by Ligation><Collaborations><Coupling><Cyclooctenes><DNA><Deoxyribonucleic Acid><Development><Environment><Family><Generations><Glycobiology><Glycoconjugates><Goals><Heating><Immunology><Industrialization><Label><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Ligation><Light><Methods><Microbiology><Modification><Molecular Interaction><N-terminal><NH2-terminal><Nitrogen><Organelles><Organism><Oxidation-Reduction><Permeability><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Photoradiation><Plant Resins><Position><Positioning Attribute><Predisposition><Preparation><Procedures><Property><Protein Binding><Protein Dynamics><Protein Engineering><Proteins><Proteomics><Radiation Chemistry><Radiochemistry><Reaction><Reagent><Redox><Reporter><Research><Rhodamine><Role><Safety><Series><Side><Site><Susceptibility><Techniques><Technology><Volatilization><Work><analog><biologic><biological therapeutic><biological treatment><biologically based therapeutics><biotherapeutics><biotherapy><bound protein><catalyst><chelation><commercialization><developmental><experiment><experimental research><experimental study><experiments><fluorophore><genetic protein engineering><improved><in vivo><interest><living system><materials science><metabolic engineering><new technology><novel><novel technologies><oxidation reduction reaction><pharmaceutical><preparations><protein design><protein purification><resin><scale up><small molecule><social role><spatiotemporal><tool><two photon excitation microscopy><two photon microscopy>