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Photocatalytic Generation of Reactive Probes for Bioconjugation and Proximity Labeling

Award Number: F32GM153032
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/10/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2025
AWARD TERMINATION DATE: 12/23/2025

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Photocatalytic Generation of Reactive Probes for Bioconjugation and Proximity Labeling - PROJECT SUMMARY Chemical modification of proteins is an important strategy for understanding their structure/function and has guided the design of new pharmaceutical products and targeted therapeutics. Accordingly, new technologies that target amino acid side chains in both selective and unselective fashions are necessary to gain advanced biochemical information. In bioconjugation processes, amino acids are selectively targeted and modified. However, classical bioconjugation strategies rely upon the inherent nucleophilicity of amino acid side chains, rendering the selective modification of less nucleophilic sites a significant challenge. At the same time, the ability to rapidly modify a variety of amino acids is necessary for proximity labeling, a strategy where proteins are tagged with reactive probes for mapping the cellular microenvironment to better understand spatial connections and relationships between biomolecules. Visible light photoredox catalysis has emerged as a powerful platform for modifying amino acids through redox events. The use of visible light as a sustainable and non-invasive stimulus not only facilitates the mild generation of reactive intermediates, but also enables spatiotemporal control over chemical reactivity, a desirable feature particularly in the treatment of disease. Nevertheless, the extension of photoredox catalysis into biological applications is underexplored because photocatalyst activation requires high- energy blue light, which penetrates tissue poorly and can result in background activation of molecules. This proposal describes the development and biological applications of red light bioconjugation and proximity labeling platforms using Os(II) photocatalysts that proceed via the conversion of small molecules into reactive probes that can react with amino acids selectively or promiscuously. A method for selective bioconjugation of aspartic acid (Asp) and glutamic acid (Glu) is described wherein red light-photoexcited Os photocatalysts activate vinyl azides into strained 2H-azirines, molecules that have been demonstrated to undergo selective reactions with carboxylates instead of other more nucleophilic groups. A unique mechanism is proposed upon reaction of a carboxylate group with photocatalytically-generated 2H-azirines to produce oxazole-derived products in the covalent modification. A variety of Os catalysts with high triplet energy values will be synthesized and evaluated in this method, which can then be translated to chemoselective labeling of these residues on peptides and proteins. The ability of this class of photocatalysts to generate carbenes from (trifluoromethyl)aryl diazos will also be explored. Reactivity will be established in the context of O–H insertion, reactions with amino acids, and in isolated proteins. Due to their reactive nature, the carbenes react with a variety of side chains rapidly, a feature that will be leveraged in tightening labeling radii in proximity labeling on cell surfaces. Proximity labeling mediated by low energy red light presents two significant advances: (1) the use of tissue-penetrating and noncytotoxic red light, and (2) minimization of any background substrate activation, enabling high precision in spatiotemporal labeling.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$39,287 )
2026	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	000	2	12/23/2025	TERMINATION	-$39,287
														Subtotal = -$39,287

Issue Date FY: 2025 ( Subtotal = $75,520 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	000	2	12/23/2024	NON-COMPETING CONTINUATION	$74,284
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	001	2	7/1/2025	NON-COMPETING CONTINUATION	$1,236
														Subtotal = $75,520

Issue Date FY: 2024 ( Subtotal = $73,828 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	001	1	1/10/2024	NEW	$0
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	002	1	5/20/2024	NEW	$4,748
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	000	1	1/10/2024	NEW	$69,080
														Subtotal = $73,828

Grand Total All Awards = $110,061

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Photocatalytic Generation of Reactive Probes for Bioconjugation and Proximity Labeling

Award Number: F32GM153032

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/10/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2025

AWARD TERMINATION DATE: 12/23/2025

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