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Mechanistic Studies of Viral Host Cell Recognition and Entry and their Implication for Protein Design of Molecular Delivery Devices

Award Number: R21AI166563
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary In the absence of selective delivery, many promising drugs do not reach the targeted cells, but rather cause toxic side effects. Many viruses, on the other hand, have mastered the art of identifying microenvironmental clues and selectively find and infect a specific cell. For instance, they depend on “local” proteases, sometimes two, to activate their fusion proteins. To develop better targeting devices, we aim to dissect molecular properties and functions embedded in viral surface proteins, specifically focusing on receptor interactions, stability, and fusion triggering (Aim I) for which we will employ surface display and infectivity assays. We will focus on the viral surface machinery of the paramyxoviruses (PMVs), specifically Parainfluenza virus 5 (PIV5). Most PMVs have a division of labor keeping host receptor binding and cell entry apart as two separate functions encoded into two molecules: one tetrameric protein responsible for molecular recognition and a trimeric fusion protein responsible for the merging of host and viral membranes. This compartmentalization makes the PMVs an excellent model system for repurposing as the fusion protein can remain untouched, while the recognition process can be re-engineered. We will take advantage of deep mutational scanning which allows us to evaluate all possible amino acid substitutions for any given genetic selection. By acquiring differential fitness landscapes for each of the aforementioned molecular properties, we will be able to address interesting questions about the biology of viruses, such as mutational tolerance in context of their protein chemistry. Importantly, fitness landscapes will have an immediate impact on engineering of delivery devices as they will provide rough blueprints of the molecular architecture of these complex machineries. We will use obtained sequence-function-structure maps for the development of a new, adaptable targeted delivery platform that will integrate viral surface machinery with antibody fragments (Aim II). The key point will be to develop an adapter molecule that integrates the antibody fragment while maintaining all regulatory function that the viral recognition machinery normally exhibits, which involves control of conformational changes. Previous efforts have not succeeded in developing an efficient, general delivery system. Here, we will obtain and leverage an invaluable database of virus protein structures together with our newly obtained sequence-function knowledge, which we combine with new technology – protein design – to advance this seemingly simple but ambitious engineering project. We aim to provide a generally applicable platform for a new targeting machinery that incorporates these molecular mechanisms while also taking advantage of the vast amount of identified and engineered antibodies. Through combining parts of the viral infection machinery with antibody fragments and adapter proteins, we anticipate that we will be able to significantly advance the development of drug and gene delivery systems and thereby also provide new and much needed precision targeting technology for genome engineering.


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: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	001	2	11/7/2023	NON-COMPETING CONTINUATION	-$1
2024	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	002	3	11/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$115,197
2024	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	1	11/7/2023	NEW	-$115,196
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $194,374 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	002	3	8/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$194,373
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	001	2	8/2/2023	NON-COMPETING CONTINUATION	-$186,485
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	2	5/16/2023	NON-COMPETING CONTINUATION	$186,486
														Subtotal = $194,374

Issue Date FY: 2022 ( Subtotal = $224,236 )
2022	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	1	6/23/2022	NEW	$224,236
														Subtotal = $224,236

Grand Total All Awards = $418,610

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Mechanistic Studies of Viral Host Cell Recognition and Entry and their Implication for Protein Design of Molecular Delivery Devices

Award Number: R21AI166563

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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