Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 27, Pages 11052-11056Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1108045108
Keywords
unnatural amino acid; protein translation; bacterial selection
Categories
Funding
- National Institutes of Health (NIH) [5R01GM062159, F32CA144213]
- National Institute of Diabetes and Digestive and Kidney Diseases, NIH
- Office of the Director, NIH
- Achievement Rewards for College Scientists Scholarship
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We report a bacterial system for the evolution of cyclic peptides that makes use of an expanded set of amino acid building blocks. Orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pairs, together with a split intein system were used to biosynthesize a library of ribosomal peptides containing amino acids with unique structures and reactivities. This peptide library was subsequently used to evolve an inhibitor of HIV protease using a selection based on cellular viability. Two of three cyclic peptides isolated after two rounds of selection contained the keto amino acid p-benzoylphenylalanine (pBzF). The most potent peptide (G12: GIXVSL; X = pBzF) inhibited HIV protease through the formation of a covalent Schiff base adduct of the pBzF residue with the.-amino group of Lys 14 on the protease. This result suggests that an expanded genetic code can confer an evolutionary advantage in response to selective pressure. Moreover, the combination of natural evolutionary processes with chemically biased building blocks provides another strategy for the generation of biologically active peptides using microbial systems.
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