Transformation of aminoacyl tRNAs for the in vitro selection of "drug-like" molecules

Chuck Merryman, Rachel Green

Research output: Contribution to journalArticlepeer-review


Evolutionary approaches are regularly used to isolate single molecules with desired activities from large populations of nucleic acids (∼10 15). Several methods have also been developed to generate libraries of mRNA-encoded peptides and proteins for the in vitro selection of functional polypeptides. In principal, such mRNA encoding systems could be used with libraries of nonbiological polymers if the ribosome can be directed to polymerize tRNAs carrying unnatural amino acids. The fundamental problem is that current chemical aminoacylation systems cannot easily produce sufficient amounts of the numerous misacylated tRNAs required to synthesize a complex library of encoded polymers. Here, we show that bulk-aminoacylated tRNA can be transformed into N-monomethylated aminoacyl tRNA and translated. Because poly-N-methyl peptide backbones are refractory to proteases and are membrane permeable, our method provides an uncomplicated means of evolving novel drug candidates.

Original languageEnglish (US)
Pages (from-to)575-582
Number of pages8
JournalChemistry and Biology
Issue number4
StatePublished - Apr 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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