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Dynamically-resolved structural studies of proteins from fungal and bacterial pathogens

Award Number: R35GM150898
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: 08/10/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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Dynamically-resolved structural studies of proteins from fungal and bacterial pathogens - Summary Drug resistance and desensitization is a growing global concern. To overcome these therapeutic issues, drug discovery pipelines have to make use of all available structural information to generate novel, potent and safe therapeutics. Current medicinal chemistry efforts typically make use of static, cryo-temperature protein structures, which do not integrate the dynamics known govern protein function. Advancing from structure-activity to dynamic-activity relationships will diversify the way we pursue drug discovery, opening doors to more advanced therapeutics. To obtain this knowledge, the projects proposed will pursue time-resolved structural studies of medically-relevant proteins from fungal and bacterial pathogens. Although challenging, time- resolved structural biology has matured over the last decade making it amenable to a wider range of protein targets. This research will break methodological barriers to swiftly obtain dynamic- activity relationships, from which we will determine how dynamics correlate to protein function. Complementary biochemical and biophysical studies will be used to unambiguously resolve protein metastable intermediates. Methods such as photocaging and cryo-trapping are used to trigger synchronize protein function in the sample, making use of the work and expertise of the PI as well as the available facilities, including a dedicated organic synthesis laboratory. Two initial targets will be pursued. The first one, C. Auris 3-Deoxy-D-arabinoheptulosonate 7- phosphate Synthase (DAHPS) is an enzyme essential for fungal survival as it catalysis a step in the biosynthesis of aromatic amino-acids. It is considered a promising drug target to current antifungals and it is dynamically allosterically regulated. The second target is rubrerythrin from B. pseudomallei, a protein believed to be responsible for oxidative stress responses for which the mechanism is still unclear. Both projects will be targeted using an overarching methodological pipeline which will generate new insights into dynamic-activity relationships and provide structures of short-lived intermediates. Beyond the cutting-edge work proposed in this grant, these discoveries will fuel a long-term research program focusing on harnessing dynamic information to drive novel drug design. The fundamental work proposed in this grant will fill gaps in our knowledge of protein mechanism and its relationship to dynamics, and will pave the way to novel drug discovery approaches. The proposed time-resolved experiments are challenging but made possible by the multi-disciplinary expertise of the PI as well as strong collaborations that drive fertile scientific discussions and unobstructed access to cutting edge technology and facilities in the USA and abroad.


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 = -$443,882 )
2024	2023	HAUPTMAN WOODWARD MEDICAL RESEARCH INSTITUTE, INC	700 ELLICOTT ST # 700	BUFFALO	NY	14203	ERIE	USA	Biomedical Research and Research Training	000	1	3/15/2024	NEW	-$443,880
2024	2023	HAUPTMAN WOODWARD MEDICAL RESEARCH INSTITUTE, INC	700 ELLICOTT ST # 700	BUFFALO	NY	14203	ERIE	USA	Biomedical Research and Research Training	001	1	6/17/2024	NEW	-$2
														Subtotal = -$443,882

Issue Date FY: 2023 ( Subtotal = $485,000 )
2023	2023	HAUPTMAN WOODWARD MEDICAL RESEARCH INSTITUTE, INC.	700 ELLICOTT ST	BUFFALO	NY	14203	ERIE	USA	Biomedical Research and Research Training	000	1	8/8/2023	NEW	$485,000
														Subtotal = $485,000

Grand Total All Awards = $41,118

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Dynamically-resolved structural studies of proteins from fungal and bacterial pathogens

Award Number: R35GM150898

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: 08/10/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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