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Chem Biol. 2004 Apr;11(4):575-82.

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

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Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Howard Hughes Medical Institute, 702A PCTB, 725 North Wolfe Street, Baltimore, MD 21205 USA.


Evolutionary approaches are regularly used to isolate single molecules with desired activities from large populations of nucleic acids (approximately 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.

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