2011
DOI: 10.1073/pnas.1108045108
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Evolution of cyclic peptide protease inhibitors

Abstract: 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… Show more

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Cited by 123 publications
(133 citation statements)
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References 37 publications
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“…For example, Benkovic and co-workers (46) have recently used this technology in combination with nonsense codon suppressor tRNA technology to build libraries of cyclic hexapeptides that include nonnatural amino acids. These libraries were screened for HIV protease inhibitors using a cell-based lethality assay (46). PTS has been also successfully used for the generation of larger circular proteins (44,47).…”
Section: Protein Backbone Cyclizationmentioning
confidence: 99%
“…For example, Benkovic and co-workers (46) have recently used this technology in combination with nonsense codon suppressor tRNA technology to build libraries of cyclic hexapeptides that include nonnatural amino acids. These libraries were screened for HIV protease inhibitors using a cell-based lethality assay (46). PTS has been also successfully used for the generation of larger circular proteins (44,47).…”
Section: Protein Backbone Cyclizationmentioning
confidence: 99%
“…This method may be generalized by using one of several "photo-caged" unnatural amino acids that have been developed to incorporate natural amino acids that are protected from posttranslational modification in similar fashion and subsequently postbiosynthetically deprotected to yield novel thiopeptides not otherwise expressible in vivo. Although no mutants were found with enhanced activity in this study, new chemical functionalities provided by ncAAs to thiopeptide biosynthesis offer the potential to screen a diverse chemical space for mutants with increased activity in the future (8,13).…”
Section: Discussionmentioning
confidence: 99%
“…However, the total synthesis of variants in sufficient quantities for mechanistic or therapeutic purposes is often time-consuming and costly. The ability to genetically encode noncanonical amino acids (ncAAs) in bacteria has provided an alternative approach to incorporating building blocks with novel structures and chemistries into ribosomally biosynthesized proteins (11), cyclic peptides (12,13), lanthipeptides (14,15), and lasso peptides (16,17). However, methods to heterologously express thiopeptides in Escherichia coli, where the genetic incorporation of ncAAs with orthogonal nonsense or frameshift suppressor aminoacyl-tRNA synthetase/tRNA (aaRS/tRNA) pairs is well-established (11), have not yet been reported.…”
mentioning
confidence: 99%
“…By screening a phage-display scFv antibody library, where six residues in the V H CDR3 were randomized, one scFv containing sulfotyrosine was obtained that binds gp120 more effectively than any similarly evolved scFv molecules containing only canonical amino acids . By screening a peptide library based on cellular viability, cyclic peptide (containing NNAA) protease inhibitors were derived (Young et al, 2011). Other NNAA-containing proteins, such as boron-containing proteins for carbohydrate binding (Liu et al, 2009), have been evolved as well.…”
Section: Functional Evolution Of Proteins With Nnaasmentioning
confidence: 99%