Tuesday, July 1, 2025 7/1/2025

Applications of Biocatalytic C–H Functionalization in Complex Molecule Synthesis

Award Number: R35GM128895
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Applications of Biocatalytic C–H Functionalization in Complex Molecule Synthesis - Project Summary Despite remarkable advances in the past decade, contemporary chemical methods for C–H oxidation and C–H functionalization still face significant challenges in achieving useful levels of selectivity on complex scaffolds. While the oxidative enzymes that have evolved to perform these transformations in Nature are capable of addressing these selectivity issues, their applications in complex molecule synthesis have been relatively limited. Seeking to bridge this gap, our lab has developed new biocatalytic C–H functionalization tools and investigated their applications in the chemoenzymatic syntheses of bioactive natural products. These tools are obtained from initial biosynthetic studies on secondary metabolites, which to date have identified a suite of unique and synthetically-useful enzymes to address unsolved C–H functionalization problems in organic chemistry. In turn, these discoveries serve as useful starting points for further activity optimization through enzyme engineering and for chemoenzymatic strategy development. Our chemoenzymatic syntheses are concise, step efficient and readily amenable to scale, demonstrating their strategic advantages. Furthermore, our achievements in the last funding period demonstrate that this strategy can be readily adapted for rapid analog generation to enable subsequent mode of action identification and structure-activity relationship studies. The current proposal outlines our long-term research program in the area of biocatalytic C–H functionalization with specific applications in natural product synthesis. Projects proposed within the program include the development of chemoenzymatic strategy to synthesize bioactive alkaloids and macrolides and explore their structure-activity relationships, the development of new biocatalytic C–H functionalization methods beyond hydroxylation and the development of a family-wide activity profiling for reaction with challenging substrates. Significant elements of innovation in this work include (1) the discovery, functional annotation and biocatalytic exploration of previously uncharacterized enzymes from various biosynthetic pathways, (2) the formulation of new chemoenzymatic strategies to access precious bioactive compounds with unsurpassed levels of efficiency, and (3) the generation of novel structural analogs for collaborative medicinal chemistry optimization and structure-activity relationship studies. More generally, the proposed work will further stimulate the development of new logic in chemical synthesis centered on the use of Nature's biocatalytic repertoire, radically altering the way chemists approach synthetic planning and allowing new small molecules to be prepared in a more efficient and practical manner.


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: 2025 ( Subtotal = $375,955 )
2025	2025	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	001	9	11/26/2024	NON-COMPETING CONTINUATION	$375,955
2025	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	000	8	11/6/2024	COMPETING CONTINUATION	$0
2025	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	003	8	1/20/2025	COMPETING CONTINUATION	$118,791
2025	2022	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	002	7	1/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$118,791
														Subtotal = $375,955

Issue Date FY: 2024 ( Subtotal = $417,727 )
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	001	8	1/31/2024	COMPETING CONTINUATION	$417,727
2024	2022	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	000	7	1/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $417,727

Issue Date FY: 2023 ( Subtotal = -$49,076 )
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	003	6	6/5/2023	NON-COMPETING CONTINUATION	-$115,646
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	6	10/27/2022	NON-COMPETING CONTINUATION	-$259,217
2023	2022	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	001	7	10/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,141
2023	2022	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Biomedical Research and Research Training	004	7	6/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$115,646
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	002	4	11/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = -$49,076

Issue Date FY: 2022 ( Subtotal = $475,000 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	002	6	6/28/2022	NON-COMPETING CONTINUATION	$475,000
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	5	6/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	4	6/1/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $475,000

Issue Date FY: 2021 ( Subtotal = $475,000 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	4	6/18/2021	NON-COMPETING CONTINUATION	$475,000
														Subtotal = $475,000

Issue Date FY: 2020 ( Subtotal = $575,000 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	001	3	5/29/2020	NON-COMPETING CONTINUATION	$475,000
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	5/26/2020	SUPPLEMENT FOR EXPANSION	$100,000
														Subtotal = $575,000

Issue Date FY: 2019 ( Subtotal = $475,000 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	6/14/2019	NON-COMPETING CONTINUATION	$475,000
														Subtotal = $475,000

Issue Date FY: 2018 ( Subtotal = $475,000 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	1	6/27/2018	NEW	$475,000
														Subtotal = $475,000

Grand Total All Awards = $3,219,606

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Applications of Biocatalytic C–H Functionalization in Complex Molecule Synthesis

Award Number: R35GM128895

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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