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. Instead of overwriting existing codons, we seek to create new ones. We have demonstrated that an unnatural base pair can be stably replicated, transcribed, and translated in a semi-synthetic organism for this purpose. With nine more codons containing an unnatural base available, we are now limited by the number and efficacy of the available orthogonal translation units to decode our codons. Therefore, the central goal of this proposal is to develop tRNA-synthetase pairs for the translation of unnatural codons. Successful completion of these aims will provide insight into RNA biology, produce orthogonal translation units that will seamlessly integrate into the semi-synthetic organism’s translational machinery, and allow the production of proteins with multiple ncAAs. The creation and use of these tRNA-synthetase pairs has the potential to revolutionize the field of protein therapeutics by providing a robust platform for the production of proteins with several ncAAs.

Engineering translational machinery for a semi-synthetic organism

2019 Fall National Meeting

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