1999
DOI: 10.1073/pnas.96.24.13638
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Production of cyclic peptides and proteins in vivo

Abstract: Combinatorial libraries of synthetic and natural products are an important source of molecular information for the interrogation of biological targets. Methods for the intracellular production of libraries of small, stable molecules would be a valuable addition to existing library technologies by combining the discovery potential inherent in small molecules with the large library sizes that can be realized by intracellular methods. We have explored the use of split inteins (internal proteins) for the intracell… Show more

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Cited by 384 publications
(416 citation statements)
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“…As well as peptides, SICLOPPS has also been used to cyclize the E. coli enzyme dihydrofolate reductase (DHFR) 20 . DHFR had been previously circularly permuted [24][25][26] and cyclized via a disulfide bond 27 .…”
Section: Anticipated Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…As well as peptides, SICLOPPS has also been used to cyclize the E. coli enzyme dihydrofolate reductase (DHFR) 20 . DHFR had been previously circularly permuted [24][25][26] and cyclized via a disulfide bond 27 .…”
Section: Anticipated Resultsmentioning
confidence: 99%
“…We have pursued intracellular backbone cyclization to generate bio-stable peptide libraries. This procedure, termed SICLOPPS 19,20 , utilizes the Synechocystis sp PCC6803 DnaE split intein 21 . By rearranging the order of the elements of the intein, an active cis-intein (I C :target peptide:I N ) is yielded that upon splicing results in cyclization of the target protein/peptide sequence (Fig.…”
Section: Introductionmentioning
confidence: 99%
“…Protein splicing in trans could ligate two foreign peptide chains that are fused with either N-or C-terminal fragments (N-or C-inteins) of a split intein [4][5][6]. Protein trans-splicing system has opened many applications including segmental isotopic labelling of proteins, protein cyclization, in vivo protein engineering, and site-specific chemical modifications [6][7][8][9][10][11][12][13][14][15]. However, protein ligation by protein trans-splicing can be significantly modulated by the junction sequences as well as by the extein sequences, which could limit the applications of protein trans-splicing [16].…”
Section: Introductionmentioning
confidence: 99%
“…PCC6803, was first successfully used for cyclization. However, similarly to the IPL/EPL approach, a mixture of linear and circular forms is obtained, presumably because of hydrolysis of an intermediate [73,75]. On the other hand, artificially split inteins such as PI-PfuI, DnaB, and the RecA intein have been successfully applied for in vivo cyclization, and only circular forms were observed [80][81][82], suggesting that the circular permutation approach is more suitable for cyclization.…”
Section: In Vivo Cyclizationmentioning
confidence: 99%
“…No mutations in the primary sequence are introduced by this method, although it might be necessary to insert a flexible linker comprising several residues to join the termini [74][75][76]. Polymer theory by Flory predicts an improvement in protein stability upon cyclization, because the entropy of the unfolded states should be reduced [77].…”
Section: Stabilizing Proteins By Intein-mediated Backbone Cyclizationmentioning
confidence: 99%