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Engineering translation machinery for a semi-synthetic organism

Award Number: F31GM128376
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2021

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Engineering translation machinery for a semi-synthetic organism - Project Summary Incorporating noncanonical amino acids (ncAAs) into proteins can grant novel properties by encoding amino acids with additional functional groups and elements, in turn, facilitating the creation of novel proteins for applications in chemical biology and protein therapeutics. Current methods for doing so can incorporate two noncanonical amino acids into proteins and seek to overwrite the current genetic code by repurposing stop or rare codons through the introduction of repurposed archaeal tRNAs and aminoacyl tRNA synthetases (aaRSs). Attempting to overwrite an existing code results in competition with the machinery adapted to the native code, in turn reducing translational fidelity. For example, repurposing tRNA/aaRS pairs from archaea has resulted in two commonly used orthogonal translation units (OTUs) that are not recognized well by the native bacterial translational machinery (including EF-Tu and ribosomes). Instead of overwriting existing codons, we seek to create new ones. We have demonstrated that an unnatural base pair (UBP) can be stably replicated in a semi- synthetic organism (SSO) for this purpose. Transcription and translation of the UBP has been successfully accomplished using the current OTUs available from archaea. With many more codons containing an unnatural base available, we are now limited by the number and efficacy of the available OTUs. Therefore, the central goal of this proposal is to develop OTUs for the translation of unnatural codons. In Specific Aim 1, the stability and orthogonality of the UBP in all sequence contexts is evaluated in RNA, providing insight into promising codons for translation. Specific Aim 2 utilizes an unnatural nucleotide in the anticodon of tRNAs as a recognition motifs to reprogram E. coli aaRSs for translation of the UBP. Finally, Specific Aim 3 will switch amino acid specificity of the aaRSs developed in Aim 2 from a canonical amino acid to an ncAA relevant for chemical biology and protein therapeutics. Successful completion of these aims will provide insight into RNA biology, produce OTUs that will seamlessly integrate into the SSO’s translational machinery, and allow the production of proteins with multiple ncAAs. The creation and use of these OTUs has the potential to revolutionize the field of protein therapeutics by providing a robust platform for the production of proteins with several ncAAs.


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: 2020 ( Subtotal = $32,520 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	3	3/27/2020	NON-COMPETING CONTINUATION	$32,520
2020	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	11/1/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $32,520

Issue Date FY: 2019 ( Subtotal = $32,016 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	3/15/2019	NON-COMPETING CONTINUATION	$32,016
														Subtotal = $32,016

Issue Date FY: 2018 ( Subtotal = $31,524 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	002	1	5/16/2018	NEW	$480
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	001	1	2/28/2018	NEW	$0
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	2/28/2018	NEW	$31,044
														Subtotal = $31,524

Grand Total All Awards = $96,060

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Engineering translation machinery for a semi-synthetic organism

Award Number: F31GM128376

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2021

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