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Synthesis and evaluation of peptidomimetics to probe the active site of the botulinum neurotoxin to discover therapeutic leads for the treatment of botulism

Award Number: R16AI175003
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/11/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Synthesis and evaluation of peptidomimetics to probe the active site of the botulinum neurotoxin to discover therapeutic leads for the treatment of botulism - Project Summary/Abstract The botulinum neurotoxin (BoNT) is the most lethal toxin known to man, with a lethal dose of only 1 ng/kg of body weight. The neurotoxin acts on neurons causing irreversible termination of neurotransmission resulting in flaccid muscle paralysis diagnosed as botulism. Botulism is a serious illness that can lead to respiratory failure and death. The intentional use of the extremely deadly neurotoxin as a biological weapon is a major concern. Coupled with limited treatment options, there is an urgent need for therapeutics to treat BoNT intoxication. The goal of this project is to create new molecules that are therapeutically sound leads for the treatment of botulism. Previously, we have discovered the dipeptide scaffold as a potent source of BoNT inhibitors via enzymatic inhibition assay and X-ray crystallography. This is the first reported example of dipeptides as a BoNT inhibitor. We propose that the dipeptide is an excellent scaffold for BoNT inhibitor design and will create dipeptides with potent inhibitor activity and optimize the pharmacokinetic properties. The aims of this proposed research are 1) Synthesize dipeptide libraries to study BoNT inhibition; 2) Evaluate the dipeptides as BoNT inhibitors through enzyme inhibition assays; 3) Examine pharmacokinetic properties of the dipeptides by performing cell permeability and metabolic stability studies. Based on the results from aims 2 and 3, structural improvements will be made to the peptides to allow for the synthesis of 2nd and 3rd-generation dipeptides that are enriched with potent inhibitors, which have excellent cell permeability and metabolic stability. Overall, the proposed research will deliver true therapeutic lead compounds with potent inhibitor activity with promising pharmacokinetic profiles. This work will provide a novel scaffold that will be a sound therapeutic lead for the treatment of botulism. Undergraduate student researchers will perform all aspects of the proposed research. Research laboratory experiences will be transformative for undergraduate students and help improve their career trajectory. The research described will provide undergraduate students with laboratory training that will be valuable for their future careers in biomedical research.


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 = $142,000 )
2025	2025	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	5/20/2025	NON-COMPETING CONTINUATION	$142,000
														Subtotal = $142,000

Issue Date FY: 2024 ( Subtotal = $131,248 )
2024	2024	CSU FULLERTON AUXILIARY SERVICES CORPORATION	1121 N STATE COLLEGE BLVD	FULLERTON	CA	92831	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	4/11/2024	NEW	$131,248
														Subtotal = $131,248

Grand Total All Awards = $273,248

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Synthesis and evaluation of peptidomimetics to probe the active site of the botulinum neurotoxin to discover therapeutic leads for the treatment of botulism

Award Number: R16AI175003

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/11/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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