Defense Date


Document Type


Degree Name

Master of Science



First Advisor

Dr. Matthew C. T. Hartman


In the quest to treat incurable diseases, peptide therapeutics take the more is better approach. That is, the more potential drugs that can be tested against a certain protein target, the better, ultimately making for quick determination of drug-like peptides. The difficulty, however, lies within the more. These peptides, translated from vast libraries, are limited by the characteristics that constitute a drug-like peptide as well as the genetic code itself.

In this paper, I address this issue of more. Using sense codon reassignment, I present a method of introducing noncanonical amino acids into translation, exponentially increasing the number of potential drug-like peptides that can be tested at once. By using synthetic tRNAs, I break the redundancy of the valine codon box, allowing for the inclusion of an unnatural amino acid into translation. Additionally, the development of a universally cell permeable sequence has allowed for libraries to gain more drug-like properties. However, these sequences are attached to linear peptide libraries. In this paper, I report a bicyclization method that tangentially expends the number of potential therapeutic peptides by granting macrocyclic libraries the same benefit. This method utilizes cyclizations compatible with in vitro translation, an already defined macrocyclic cell penetrating peptide (CPP), and a cyclic therapeutic cargo sequence to create interlocking rings for improved permeability.


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Available for download on Tuesday, December 12, 2028