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Bioconjugations Employing Unnatural Amino Acids

Award Number: R15GM113203
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: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Bioconjugations Employing Unnatural Amino Acids - Project Abstract The ability to prepare well-defined protein/small-molecule/solid-support bioconjugates possesses significant advantages in the treatment and diagnosis of a variety of diseases. However, several issues associated with the preparation of the bioconjugates preclude their widespread application. This proposal aims to address these issues via the use of unnatural amino acid technologies to rapidly synthesize highly active and well- defined conjugates. Specifically, a variety of unnatural amino acids will be synthetically prepared and assessed for their utility in bioconjugations. First, utilizing pre-existing UAAs, novel bioconjugations will be developed and optimized under physiological conditions, including the Glaser Hay coupling between terminal alkynes and the [2+2+2] cyclotrimerization between three alkynyl moieties. Secondly, a set of amino acids with reactive moieties (alkyne, azide, aminooxy, aldehyde etc) will be prepared to improve the efficiency of the bioconjugation reactions and prepare multivalent conjugates. Following the synthesis and in vitro assessment of these novel amino acids, they will be evaluated for site-specific incorporation into model proteins using evolved aminoacyl tRNA synthetase/tRNA pairs. Utilizing optimized conditions, both model and medically relevant proteins will be immobilized onto solid-supports using the technologies to develop diagnostic protein chips. Finally, the developed technologies can be combined to produce multivalent bioconjugates that provide numerous therapeutic properties inaccessible to standard bivalent conjugates. This includes the linking of an antibody targeting agent to a small molecule drug and a fluorophore to be able to track drug delivery; however, there are numerous other applications of multivalent conjugates that can also be envisioned. Ultimately, the methodologies will be transitioned to biologically relevant systems including ubiquitin binding proteins, esterases, antibodies, and Cas9/dCas9. The tools developed within the proposed research will not only significantly advance the fields of therapeutics and diagnostics, but also be extremely useful in the training of undergraduate researchers towards their future careers within the scientific arena.


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 = $0 )
2025	2020	COLLEGE OF WILLIAM AND MARY	1314 S MOUNT VERNON AVE	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Biomedical Research and Research Training	000	2	1/29/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	COLLEGE OF WILLIAM AND MARY	1314 S MOUNT VERNON AVE	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Biomedical Research and Research Training	000	2	5/26/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2016	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Biomedical Research and Research Training	000	1	9/28/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $324,678 )
2020	2020	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Biomedical Research and Research Training	002	2	7/10/2020	COMPETING CONTINUATION	$324,678
2020	2016	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Biomedical Research and Research Training	000	1	3/24/2020	NEW	$0
2020	2016	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Biomedical Research and Research Training	001	1	7/9/2020	NEW	$0
														Subtotal = $324,678

Issue Date FY: 2016 ( Subtotal = $352,472 )
2016	2016	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Biomedical Research and Research Training	000	1	3/11/2016	NEW	$352,472
														Subtotal = $352,472

Grand Total All Awards = $677,150

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Bioconjugations Employing Unnatural Amino Acids

Award Number: R15GM113203

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: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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