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Precision Glycopolymer Bacteriochlorin Conjugates for Probing HA-CD44 Interactions

Award Number: R15GM119067
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: 09/15/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Precision Glycopolymer Bacteriochlorin Conjugates for Probing HA-CD44 Interactions - DESCRIPTION (provided by applicant) Precision Glycopolymer Bacteriochlorin Conjugates for Probing HA-CD44 Interactions Project Summary/Abstract One of the major challenges in studying carbohydrate-protein interactions is the low binding affinity of individual carbohydrate subunits. Molecular scaffolds that mimic glycoconjugates can be useful for studying these processes. However, the lack of reliable and reproducible methods for the preparation of precise, well- defined molecular scaffolds has so far limited the development of these compounds. Our proposed fundamental research aims to overcome these limitations through the modular synthesis and evaluation of a series of well-defined, tunable bacteriochlorin conjugates that can be used to systematically probe carbohydrate-protein interactions. The primary goal of our research is to synthesize oligoproline scaffolds bearing bacteriochlorins and differentially-functionalized hyaluronic acid (HA) disaccharides. These so-called hyaluronic acid bacteriochlorin-based oligoproline conjugates (HABOCs) will be used to study how HA presentation impacts its recognition by glycoprotein CD44. We chose to study this interaction between HA and CD44 because of its importance in human health and diseases, including tumor metastasis. The HA-CD44 interaction is responsible for both pro- and anti-inflammatory properties, can promote or inhibit cell migration, and can activate or stop cell division and differentiation. Interestingly, these seemingly disparate roles have been shown to be regulated by factors that involve specific cell types as well as the location and size (native high molecular weight (HMW) vs lower molecular weight oligosaccharides (oHA)) of HA. What is lesser known is whether HA presentation impacts HA-CD44 binding. Our research aims to answer this question. The second goal of our studies is to determine whether we can exploit the HABOC interaction to develop cell penetrating phototheranostics that use CD44 receptor-mediated endocytosis. The bacteriochlorin, which absorbs in the NIR between 700-800nm, shows significant promise as a next generation theranostic for image-guided and photodynamic therapies. We hypothesize that HABOCs can be designed to precisely present HA to mimic HMW-HA and o-HA binding, that these HABOCs will interact differently with cells expressing different levels of CD44, and that our HABOCs can be used to quantify cell uptake and inactivation via photodynamic therapy (PDT). With the aforementioned hypotheses in mind, our specific aims are: (i) To synthesize a series of well- defined, hyaluronic acid bacteriochlorin-based oligoproline conjugates (HABOCs), (ii) To evaluate HABOC- CD44 interactions using isothermal titration calorimetry (ITC) and saturation transfer difference (STD) NMR, and (iii) To conduct cellular uptake and phototoxicity studies to determine whether HABOCs interact with cell lines expressing different levels of CD44 and whether this interaction can be used to inactivate cells using PDT. Our research addresses the questions: "How does HA length and presentation impact the HA-CD44 interaction?" and "Can we use HABOCs to selectively target cells with different levels of CD44 expression?"


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 = -$5,578 )
2023	2016	THE TRUSTEES OF DAVIDSON COLLEGE	209 RIDGE RD	DAVIDSON	NC	28036	MECKLENBURG	USA	Biomedical Research and Research Training	000	1	10/1/2022	NEW	-$5,578
														Subtotal = -$5,578

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2016	TRUSTEES OF DAVIDSON COLLEGE, THE	209 RIDGE RD	DAVIDSON	NC	28035	MECKLENBURG	USA	Biomedical Research and Research Training	000	1	11/16/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2016	TRUSTEES OF DAVIDSON COLLEGE, THE	209 RIDGE RD	DAVIDSON	NC	28035	MECKLENBURG	USA	Biomedical Research and Research Training	000	1	3/10/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2016	TRUSTEES OF DAVIDSON COLLEGE, THE	209 RIDGE RD	DAVIDSON	NC	28035	MECKLENBURG	USA	Biomedical Research and Research Training	000	1	8/31/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $406,485 )
2016	2016	DAVIDSON COLLEGE	POST OFFICE BOX 1568	DAVIDSON	NC	28036	MECKLENBURG	USA	Biomedical Research and Research Training	000	1	9/12/2016	NEW	$406,485
														Subtotal = $406,485

Grand Total All Awards = $400,907

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Precision Glycopolymer Bacteriochlorin Conjugates for Probing HA-CD44 Interactions

Award Number: R15GM119067

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: 09/15/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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