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Biosynthesis of the Leinamycin Family of Natural Products: Mechanistic Studies and Chemoenzymatic Analog Synthesis

Award Number: F32GM133114
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/16/2019
PERIOD OF PERFORMANCE END DATE: 05/15/2022

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Biosynthesis of the Leinamycin Family of Natural Products: Mechanistic Studies and Chemoenzymatic Analog Synthesis - PROJECT SUMMARY/ABSTRACT Chemotherapy has been the centerpiece of cancer treatment in modern society, and will remain so for the foreseeable future. DNA-damaging compounds have seen the most use historically in this regard, due to cancer cells’ increased rates of growth and proliferation relative to normal, healthy cells. However, these treatments often cause off-target effects and resistance development. Therefore, compounds that can damage cancer cell DNA in a selective fashion and with a mechanism complementary to current clinical treatments offer solutions to both of these issues. The natural product leinamycin (LNM) is a DNA-damaging compound that only elicits its DNA-damaging effects upon activation by thiols, and has nanomolar activity against tumor cells resistant to clinically utilized drugs. LNM E1 is an engineered LNM analog that upon activation by reactive oxygen species (ROS) exerts its antitumor activity via a mechanism orthogonal to LNM. A single scaffold that can be primed for DNA damage in two complementary ways is unique to this set of compounds, and sets the stage for further optimization of the LNM scaffold in terms of anticancer activity. The biosynthetic origin of LNM in Streptomyces has been an area of intense study, and many of the biosynthetic steps have been elucidated and led to discoveries involving unprecedented chemical steps. The long-term goals of this project are to harness the power of a mechanistic understanding of LNM biosynthesis to genetically alter producing organisms for production of analogs with improved therapeutic properties. This proposal contains two aims: (i) investigate the mechanism of a key biosynthetic step and (ii) access rationally-designed analogs of both LNM and LNM E1 to answer specific questions about the compounds’ biological activities. The central hypothesis of this proposal is that LNM compounds can be tuned and improved in both stability and potency through rational design. This hypothesis is rationalized by Nature’s ability to produce an array of LNM-type compounds, which have served as the inspiration for the structural changes proposed herein. The outcomes of this application will be a mechanistic understanding of one of the key steps of LNM biosynthesis and access to novel LNM analogs that can be used to answer key questions about LNM DNA-damaging and anticancer activity. These findings can be applied to the long-term goal of rational biosynthetic manipulation to produce targeted structural LNM analogs for further anticancer development.


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: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	4	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	3	5/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	4	6/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$7,867
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	3	6/2/2022	NON-COMPETING CONTINUATION	-$7,867
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $68,562 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	3	4/5/2021	NON-COMPETING CONTINUATION	$68,562
														Subtotal = $68,562

Issue Date FY: 2020 ( Subtotal = $65,310 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	3/31/2020	NON-COMPETING CONTINUATION	$65,310
														Subtotal = $65,310

Issue Date FY: 2019 ( Subtotal = $61,226 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	001	1	4/18/2019	NEW	$0
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	1	4/18/2019	NEW	$61,226
														Subtotal = $61,226

Grand Total All Awards = $195,098

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Biosynthesis of the Leinamycin Family of Natural Products: Mechanistic Studies and Chemoenzymatic Analog Synthesis

Award Number: F32GM133114

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/16/2019

PERIOD OF PERFORMANCE END DATE: 05/15/2022

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