Wednesday, July 9, 2025 7/9/2025

Understanding and controlling the cellular fate of fluorine-modified biologics

Award Number: R35GM142902
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Understanding and controlling the cellular fate of fluorine-modified biologics - PROJECT SUMMARY Organofluorine compounds possess attractive chemical, pharmacological and biological properties that have allowed them to make paradigm shifts in the design of biopharmaceuticals and biologic materials. The introduction of fluorine atoms into amino acids and nucleic acids opens a vast new chemical landscape with which to alter the folding, stability, oligomerization propensity and bioactivity of peptides, proteins and DNA. However, although shown to impart favorable properties, the impact of adding fluorine into biologic scaffolds is rarely predictable. Further, increasing evidence suggests perfluorinated compounds promiscuously adsorb to many of the fundamental building blocks of cells - including lipids, proteins and DNA - to elicit a plurality of bioeffects. One of these effects, recently discovered by the PI’s lab, is the ability of organofluorine molecules to direct protein and DNA assembly into fluorous microdomains that phase separate into fluorinated liquids without denaturing the biologic. The PI has recently exploited these emergent properties to enable ultrasound-guidance of fluorinated proteins in three-dimensional tissues. Building upon these preliminary findings, the proposed research program will mechanistically explore how organofluorine compounds influence the structure and function of adsorbed proteins and DNA and use these insights to guide the design of new supramolecular assembled biomaterials. Our overarching hypothesis is that organofluorine compounds non-covalently adsorb to proteins and DNA to direct their separation into fluorine-rich phases, which in turn alters their oligomeric assembly, cellular fate and bioactivity. To test this assertion, we will expand our perfluorinated compound (PFC) library to include a diversity of molecules with basic/acidic functionalities and heterocyclic moieties. We will use this library to establish structure-activity relationships governing the ability of PFCs to adsorb proteins, and investigate how PFC complexation alters protein cellular uptake, intracellular trafficking and bioactivity. In parallel, we will use this library to study the molecular mechanisms mediating PFC-DNA interactions and examine how PFC complexation alters DNA stability and metabolic homeostasis in exposed cells. Together, these studies will establish a comprehensive mechanistic understanding of how PFCs interact with proteins and DNA and will allow us to rationally design fluorous biotechnologies that exploit the unusual assembly phenomenon and phase- separation properties that emerge. As an example, we will create ultrasound-sensitive fluorine nanoemulsions loaded with PFC-modified ribonucleoproteins (RNPs) to enable imaging-guided gene editing in kidney tissue. Success of this research will advance the use of PFCs as a new molecular motif to control protein and DNA assembly, and the methods developed applied to discover new reagents for intracellular transduction of fluorinated biomacromolecules. Ultimately, advancing knowledge on how organofluorine compounds interact with proteins and DNA, and its effects on cells, will guide the rational design of new PFC enabled technologies with desirable functional properties for drug discovery and nanomedicine applications.


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 = $381,376 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	5	7/1/2025	NON-COMPETING CONTINUATION	$381,376
														Subtotal = $381,376

Issue Date FY: 2024 ( Subtotal = $381,515 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	6/26/2024	NON-COMPETING CONTINUATION	$381,515
														Subtotal = $381,515

Issue Date FY: 2023 ( Subtotal = $381,654 )
2023	2023	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	8/29/2023	NON-COMPETING CONTINUATION	$381,654
														Subtotal = $381,654

Issue Date FY: 2022 ( Subtotal = $392,240 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	6/22/2022	NON-COMPETING CONTINUATION	$392,240
														Subtotal = $392,240

Issue Date FY: 2021 ( Subtotal = $407,000 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	6/28/2021	NEW	$407,000
														Subtotal = $407,000

Grand Total All Awards = $1,943,785

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Understanding and controlling the cellular fate of fluorine-modified biologics

Award Number: R35GM142902

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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