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Development of Transfer Hydrogenation Small-Molecule Intracellular Metal Catalysts (SIMCats) and their Application Toward Toxic Aldehyde Remediation

Award Number: R01GM129276
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Although small-molecule intracellular metal catalysts (SIMCats) offer potentially powerful new ways to manipulate biological systems, several scientific barriers to their development have unfortunately limited their use in life science research. The long-term goal of this project is to establish a comprehensive SIMCat discovery program that focuses on their development and translation from the reaction flask to living systems. The overall objectives of this research are to 1) identify the factors that are important to obtaining fast, selective, and biocompatible transfer hydrogenation SIMCats; and 2) create new catalytic agents for the remediation of aldehyde overload. We are interested in SIMCats that catalyze transfer hydrogenation reactions because they mimic important redox enzymes that are ubiquitous in all life forms. Our central hypothesis is that these synthetic enzyme mimics could be used to neutralize toxic aldehydes in vivo so that endogenous antioxidants, such as glutathione, are free to sequester reactive oxygen species that damage cells and tissue. The rationale for this project is that by selectively converting toxic aldehydes to non-toxic alcohols, transfer hydrogenation SIMCats could supplement Nature’s defense system against oxidative stress. SIMCats are expected to be highly efficient detoxification agents due to their ability to catalyze continuous reaction turnovers, unlike conventional aldehyde scavengers that get consumed upon each reaction. In Specific Aim 1, a variety of half-sandwich metal complexes will be tested for their activity and the most promising candidates will be subjected to structure-activity relationship and kinetic/thermodynamic studies to obtain chemical insights into their catalytic behavior. In Specific Aim 2, the catalytic rates, speciation, and distribution of SIMCats inside live cells will be determined. This aim will be accomplished by taking advantage of single-molecule super resolution microscopy and ratiometric fluorescence imaging techniques to visualize SIMCats “in action.” In Specific Aim 3, the ability of transfer hydrogenation SIMCats to protect neuroblastoma cells and zebrafish against aldehyde toxicity will be evaluated. The efficacy and aldehyde selectivity of SIMCat detoxification agents will be compared to that of conventional stoichiometric aldehyde traps. The significance of our research is the development of synthetic methodologies that are tailored toward the discovery of novel SIMCats, which considers not only chemical reactivity and substrate selectivity but also biocompatibility. The innovation of our research is the application of organometallic complexes to protect cells against chemical toxicants by exploiting their catalytic capabilities. We expect that this work will help streamline the SIMCat discovery process and lead to new approaches to remedy aldehyde overload, which could have important therapeutic relevance to the treatment of oxidative stress-related diseases in humans.


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: 2024 ( Subtotal = $275,400 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	5	2/15/2024	NON-COMPETING CONTINUATION	$275,400
														Subtotal = $275,400

Issue Date FY: 2023 ( Subtotal = $306,000 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	4	4/25/2023	NON-COMPETING CONTINUATION	$306,000
														Subtotal = $306,000

Issue Date FY: 2022 ( Subtotal = $306,000 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	001	3	7/21/2022	NON-COMPETING CONTINUATION	$30,600
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	3	2/10/2022	NON-COMPETING CONTINUATION	$275,400
														Subtotal = $306,000

Issue Date FY: 2021 ( Subtotal = $306,000 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	2	2/12/2021	NON-COMPETING CONTINUATION	$306,000
														Subtotal = $306,000

Issue Date FY: 2020 ( Subtotal = $306,000 )
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Biomedical Research and Research Training	000	1	4/2/2020	NEW	$306,000
														Subtotal = $306,000

Grand Total All Awards = $1,499,400

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Development of Transfer Hydrogenation Small-Molecule Intracellular Metal Catalysts (SIMCats) and their Application Toward Toxic Aldehyde Remediation

Award Number: R01GM129276

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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