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New Methods for Synthesizing Bioactive Peptides

Award Number: R15GM114789
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: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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New Methods for Synthesizing Bioactive Peptides - Project Summary Advances in organic synthesis have enabled the construction of increasingly complex peptide drugs and natural products. However, access to many important peptides is still hindered or prevented by limitations in current methods. Accordingly, the objective of this project is to discover new synthetic methods and apply them to constructing bioactive peptide natural products. The hypothesis is that the proposed methods will enable efficient construction of peptides that will be used to accelerate advances in medicinal chemistry and chemical biology. The rationale for this idea is that pushing back the frontiers of peptide synthesis will unlock access to unexplored areas of peptide chemical space, providing valuable new tools to medicinal chemists and chemical biologists in the fight against disease. The hypothesis will be tested by pursuing three Specific Aims. Aim 1 involves devising a universal method of synthesizing ,-dehydroamino acids and streamlining their incorporation into peptides. Eliminations of -nitroamino acids will be explored for this purpose. The process will first be optimized in solution with model tripeptide substrates. Then, on-resin eliminations will be developed in the context of a library of tunicyclin B analogs. Aim 2 entails determining the structure of the anticancer peptide prethioviridamide through synthesis of the candidate diastereomers. A convergent approach involving late-stage coupling of macrocycles and thioamide-rich hexapeptides will be pursued. The macrocycles will be synthesized in solution, and the hexapeptides will be assembled on solid support. Aim 3 consists of developing a new serine ligation protocol. The combination of carboxylate alkylation and O-to-N acyl transfer will be used to ligate peptide segments and achieve macrocyclizations, with both processes occurring without epimerization. Various electrophiles and N-methylated nucleophiles will be studied. Cyclic peptides ranging from four to eight residues will be targeted by the macrocyclization investigation. The approach is innovative because it features the development of novel synthetic methods such as eliminations of resin-bound -nitroamino acids, convergent couplings of macrocyclic -thioenamides with linear polythioamides, and ligations that use the carboxylate as a nucleophile instead of an electrophile. The significance of the proposed research lies in its ability to facilitate the synthesis of peptides that can be used to solve important medicinal chemistry and chemical biology problems. Such studies could include the use of ,-dehydroamino acids to impart rigidity and proteolytic stability to bioactive peptides, the design and synthesis of potent and stable analogs of prethioviridamide as anticancer agents, and the synthesis of medicinally relevant peptides via epimerization-free serine ligations. This project is envisioned to create new synthetic methods that will facilitate exciting advances in medicinal chemistry and chemical biology.


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 = $0 )
2025	2024	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	001	3	3/26/2025	COMPETING CONTINUATION	$3
2025	2020	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	2	3/26/2025	COMPETING CONTINUATION	-$3
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $440,904 )
2024	2024	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	3	6/21/2024	COMPETING CONTINUATION	$440,904
														Subtotal = $440,904

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	BRIGHAM YOUNG UNIVERSITY	A-153 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	2	5/8/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2016	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	1	1/31/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $436,500 )
2020	2020	BRIGHAM YOUNG UNIVERSITY	A41 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	2	7/13/2020	COMPETING CONTINUATION	$436,500
														Subtotal = $436,500

Issue Date FY: 2018 ( Subtotal = $67,295 )
2018	2018	BRIGHAM YOUNG UNIVERSITY	A-41 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	1	4/4/2018	SUPPLEMENT FOR EXPANSION	$67,295
														Subtotal = $67,295

Issue Date FY: 2016 ( Subtotal = $435,000 )
2016	2016	BRIGHAM YOUNG UNIVERSITY	D-177 ASB	PROVO	UT	84602	UTAH	USA	Biomedical Research and Research Training	000	1	7/12/2016	NEW	$435,000
														Subtotal = $435,000

Grand Total All Awards = $1,379,699

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New Methods for Synthesizing Bioactive Peptides

Award Number: R15GM114789

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: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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