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Biosynthetic Development and Diversification of Moroidin Peptides for Cancer Applications

Award Number: F31GM155959
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 09/02/2025

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Biosynthetic Development and Diversification of Moroidin Peptides for Cancer Applications - PROJECT SUMMARY Macrocyclic peptides are effective scaffolds for cancer drug discovery because they can combine the metabolic stability and target specificity of biologics with oral bioavailability and membrane permeability of small molecules. The bicyclic octapeptide moroidin is a promising lead structure for anticancer therapy. Moroidin is characterized by an N-terminal pyroglutamate and two tryptophan side-chain cross-linkages. Due to low-yield isolation from source-plant material and synthetic challenges toward macrocyclic complexity and chirality, an optimized biosynthetic route is needed to diversify and produce moroidin analogs in a heterologous expression system. Moroidin is a ribosomally synthesized and post-translationally modified peptide derived from autocatalytic Japanese kerria peptide cyclase KjaBURP, which installs the tryptophan-crosslinks to a leucine and a histidine side chain in a copper-dependent reaction. KjaBURP encodes four moroidin core peptide motifs attached to the C-terminal catalytic BURP domain. Based on preliminary work, I hypothesize that the second moroidin ring can be exploited to generate hundreds of analogs with chemopreventative potential. In Specific Aim 1, metabolic engineering of the moroidin pathway via heterologous expression of moroidin cyclase constructs such as KjaBURP in Nicotiana benthamiana will maximize biosynthetic access to natural moroidins and its analogs. Specific Aim 2 seeks to generate a small library of semi-pure moroidin analogs in transgenic tobacco by engineered KjaBURP, test their cytotoxic activity against cancer cell lines, and use various high-throughput scoring methods to propose a mechanism of action for dose-responsive peptides. The proposed research of moroidin pathway engineering is an approach to generate and biologically screen new plant peptide libraries for utility in cancer drug discovery.


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: 2026 ( Subtotal = -$49,537 )
2026	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	12/4/2025	NON-COMPETING CONTINUATION	-$49,537
														Subtotal = -$49,537

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	2	8/11/2025	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	001	1	6/20/2024	NEW	$0
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Biomedical Research and Research Training	000	1	6/20/2024	NEW	$48,974
														Subtotal = $48,974

Grand Total All Awards = $48,975

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Biosynthetic Development and Diversification of Moroidin Peptides for Cancer Applications

Award Number: F31GM155959

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 09/02/2025

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