# Exploring the Limits of Ribosome Mediated Polymerizations for Expanding the Genetic Code

> **NIH NIH F31** · UNIVERSITY OF TEXAS AT AUSTIN · 2021 · $37,916

## Abstract

PROJECT SUMMARY
 Recombinant protein production (RPP) has become a powerful tool for producing life-saving
therapeutics such as insulin, monoclonal antibodies, and other critical biopharmaceuticals. However, this
promising technology is severely limited by the ability to efficiently expand the genetic code to incorporate
exotic monomers and backbones for enhanced therapeutic function. The vast majority of biopolymers currently
produced by the translation machinery display polyamide backbones; therefore, the possible secondary and
tertiary confirmations available to proteomimetics synthesized via RPP are limited to these scaffolds. Since
monomer sequence defines structure and structure defines function, expanding the available monomer pool for
translation will produce biopolymers with greater structural complexity and thus increase the functional
capabilities for proteomimetic therapeutics. A major limitation to addressing this issue is the underexplored
capability of the ribosome to incorporate unnatural monomers, especially those that do not form peptide
(amide) bonds. Toward this goal, this proposal aims to develop genetically encoded chemistries that can be
catalyzed by the ribosome to synthesize sequence defined polymers (SDPs) with structurally diverse
backbones (non-peptide bonds).
 Specifically, I will design and synthesize a library of a-hydrazino-keto ester monomers, charge them
onto orthogonal tRNA, introduce them to the translation machinery in vitro, and evaluate the ability of the
ribosome to catalyze their polymerizations. The hydrazine and keto ester moieties are known to react in
solution to form various heterocyclic products. Importantly, the last mechanistic step in heterocyclic formation is
amide bond formation, a specialty of the ribosome. Therefore, I hypothesize that bifunctional monomers
comprised of both these moieties are capable of forming heterocyclic linkages via ribosome mediated
catalysis. Encouraging preliminary results by our collaborative and interdisciplinary research team have
suggested this goal is achievable as we have found the ribosome to be more accommodating than previously
thought. The experiments in this proposal will (1) broaden our understanding of molecular translation, (2)
elucidate the limitations and principles that govern genetic code reprogramming, and (3) expand the synthetic
toolbox for the development of biologically derived SDPs via the ribosome. Accomplishing the aims in this
proposal will increase the backbone diversity currently attainable by the translation machinery and could
produce SDPs that might exhibit greater therapeutic efficacy.

## Key facts

- **NIH application ID:** 10148199
- **Project number:** 1F31GM140662-01
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Jaime N Coronado
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $37,916
- **Award type:** 1
- **Project period:** 2021-01-25 → 2024-01-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148199

## Citation

> US National Institutes of Health, RePORTER application 10148199, Exploring the Limits of Ribosome Mediated Polymerizations for Expanding the Genetic Code (1F31GM140662-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148199. Licensed CC0.

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