Quadruplet Decoding for Multiplexed Non-Canonical Amino Acid Incorporation

多重非规范氨基酸掺入的四联体解码

基本信息

项目摘要

Project Summary/Abstract Protein therapeutics have played an ever-increasing role in drug discovery during the past 20 years, leading to some 380 FDA-approved drugs on the market today. All these biologics use only the tiny fraction of chemical space accessible to the standard 20 amino acids. The ability to incorporate Non-Canonical Amino Acids (NCAAs) into protein therapeutics is a promising strategy that would greatly improve the chemical sophistication of biologics, increase their bioavailability through cyclization or PEGylation, and facilitate chemical conjugation to create immunoconjugates. NCAA incorporation can be accomplished both in vitro and in vivo, but the cost of in vitro systems renders them unsuitable for production of therapeutics at scale, and cellular production is crippled by the lack of free triplet codons. I propose to harness powerful new directed evolution techniques to develop a method capable of efficiently incorporating numerous NCAAs into proteins in vivo, thereby paving the way toward low-cost, chemically-diverse protein therapeutics. Techniques in use today are limited to incorporation of no more than two NCAAs into the same protein chain. Here, I aim to improve upon this technical capability. If successful, this approach will pave the way toward production of genetically-encoded materials entirely composed of NCAAs, a technical capability that would have immediate applications for therapeutics as well as material science more broadly. I focus on frameshift suppression, an extensible technique for NCAA incorporation that offers 256 codons, rather than just two. I propose to develop a reporter for frameshift suppression, allowing me to quantify suppression efficiency more robustly than was previously possible. Next, I propose to evolve two independent molecular targets that limit frameshift suppression efficiency: suppressor tRNAs and ribosomal rRNA, in favor of improved efficiency. Existing work with traditional engineering and small libraries has seen modest success already toward the goal of improved efficiency, suggesting that my approach, which leverages a powerful continuous evolution technique, will be successful. Together, this project investigates an extensible approach to the important capability of NCAA incorporation, and aims to develop technology capable of alleviating technical difficulties that presently limit the utility of this approach.
项目总结/摘要 在过去的20年里,蛋白质治疗在药物发现中发挥了越来越大的作用, 导致目前市场上约有380种FDA批准的药物。所有这些生物制剂只使用了 标准20种氨基酸的化学空间。结合非规范氨基的能力 将NCAAs引入蛋白质治疗是一种很有前途的策略, 生物制剂的复杂性,通过环化或PEG化增加其生物利用度,并促进 化学缀合以产生免疫缀合物。NCAA掺入可以在体外和体外完成。 但是体外系统的成本使得它们不适合大规模生产治疗剂,并且 细胞生产因缺乏游离三联体密码子而受到削弱。我建议利用强大的新的指导 进化技术,以开发一种能够有效地将许多NCAAs整合到蛋白质中的方法, 体内,从而为低成本,化学多样性蛋白质治疗铺平了道路。 目前使用的技术仅限于将不超过两种NCAAs掺入同一蛋白质中 链在这里,我的目标是提高这种技术能力。如果成功,这种方法将为 生产完全由NCAAs组成的遗传编码材料,这是一种技术能力, 将立即应用于治疗学以及更广泛的材料科学。我专注于 移码抑制,一种可扩展的NCAA掺入技术,提供256个密码子,而不仅仅是 两个.我建议开发一个用于移码抑制的报告器,使我能够量化抑制效率 比以前可能的更强大。接下来,我建议进化出两个独立的分子靶点, 限制移码抑制效率:抑制tRNA和核糖体rRNA,有利于提高效率。 传统工程和小型库的现有工作已经朝着这个目标取得了一定的成功 提高效率,这表明我的方法,它利用了一个强大的持续发展, 技术,一定会成功。总之,这个项目研究了一种可扩展的方法, NCAA公司的能力,旨在开发能够减轻技术困难的技术 这目前限制了该方法的实用性。

项目成果

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Erika Alden DeBenedictis其他文献

The case for Mars terraforming research
火星地球化研究的案例
  • DOI:
    10.1038/s41550-025-02548-0
  • 发表时间:
    2025-05-13
  • 期刊:
  • 影响因子:
    14.300
  • 作者:
    Erika Alden DeBenedictis;Edwin S. Kite;Robin D. Wordsworth;Nina L. Lanza;Charles S. Cockell;Pamela A. Silver;Ramses M. Ramirez;John Cumbers;Hooman Mohseni;Christopher E. Mason;Woodward W. Fischer;Christopher P. McKay
  • 通讯作者:
    Christopher P. McKay

Erika Alden DeBenedictis的其他文献

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