Diverse backbone-cyclized peptides via codon reprogramming

Kawakami, Takashi; Ohta, Atsushi; Ohuchi, Masaki; Ashigai, Hiroshi; Murakami, Hiroshi; Suga, Hiroaki

doi:10.1038/nchembio.259

Cited by 149 publications

(173 citation statements)

References 25 publications

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“…previously used for elongation in nonsense suppression, but also D-amino acids, 52 N-methylamino acids, 21,44,51 and peptoids (N-alkylglycine) 22 which have been otherwise known to be notoriously difficult substrates. Additionally, diverse kinds of N-acylamino acids, such as L-and D-amino acids 23,24 and exotic peptides 26 have been used for the initiation to express Nterminal-modified peptides.…”

Section: 41mentioning

confidence: 99%

“…Following translation, the Nchloroacetyl group at the N-terminus is spontaneously reacted with the side chain sulfhydryl group of a downstream cysteine to generate a macrocyclic peptide via a thioether bond. We have also developed other methods of backbone macrocyclization, such as macrocyclization via diketopiperadine formation 51,53 and bicyclization the combined use of the thioether bond forming reaction and a Huisgen reaction 49 or selective disulfide bond formation.…”

Section: 41mentioning

confidence: 99%

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Flexizymes-facilitated Genetic Code Reprogramming Leading to the Discovery of Drug-like Peptides

Terasaka

Suga

2013

Chemistry Letters

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Flexizymes are a family of aminoacylation ribozymes devised by in vitro selection in our research group. They charge a wide variety of nonproteinogenic amino acids onto virtually any kind of tRNAs, enabling us to reprogram the genetic code in a custom-made cell-free translation system. This genetic code reprogramming method was integrated with a mRNA display method, which not only expresses nonstandard peptides such as macrocyclic peptides but also selects ligands specifically binding to target proteins. This system is referred to as random nonstandard peptide integrated discovery (RaPID) system, which has yielded inhibitors against disease-related target proteins. In this review, we summarize the evolutionary history and recent applications of the flexizymes and RaPID system.

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Section: 41mentioning

confidence: 99%

Section: 41mentioning

confidence: 99%

Flexizymes-facilitated Genetic Code Reprogramming Leading to the Discovery of Drug-like Peptides

Terasaka

Suga

2013

Chemistry Letters

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“…16 The linear peptide undergoes cyclization via nucleophilic attack from the N-terminus to an electrophilic substituent on the C-terminus. 48 A variety of chemical reactions has been employed for this purpose; for example, incorporation of a C-terminal cysteine or proline leads to N-S and O-N acyl shifts, generating a thio-ester with which an N-terminal nucleophile will spontaneously react to form a cyclic product ( Figure 4). 49 Scaffolded and polycyclic peptides can also be designed through the incorporation of adjacent cysteine residues that react in situ to generate constrained ring structures.…”

Section: Fit and Rapidmentioning

confidence: 99%

“…49 Scaffolded and polycyclic peptides can also be designed through the incorporation of adjacent cysteine residues that react in situ to generate constrained ring structures. 48,50 Incorporation of unnatural amino acids can also be used for the cyclization reaction, using techniques such as oxidative coupling, click chemistry, and Michael additions. 47 Such cyclization events can be programmed into the sequence by the addition of the relevant reactive species to the desired amino acid in the chain.…”

Section: Fit and Rapidmentioning

confidence: 99%

Methods for the Creation of Cyclic Peptide Libraries for Use in Lead Discovery

et al. 2015

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A surprisingly high number of drug discovery projects begin with a peptide as the initial hit.1-4 These starting molecules typically need significant chemical development as linear peptides have poor pharmacokinetic properties (e.g., oral bioavailability and stability to peptidases). 5,6 Cyclic peptides, however, are far less susceptible to proteolysis 7 and often have increased biological activity because of their conformational rigidity, which decreases entropic loss upon binding. 8,9 In contrast to (and possibly as a result of) their relative underutilization in industry, cyclic peptide libraries have been extensively employed in academia, with multiple approaches developed for their generation. Such work has demonstrated the suitability of the cyclic peptide scaffold for the identification of inhibitors against some of the most challenging targets, including protein-protein interactions (PPIs).10 Macrocyclic peptide scaffolds appear to be optimal for this purpose, and with genetically encoded cyclic peptide libraries in particular, 11,12 there is potential for the straightforward creation of large sequence diversity (e.g., 6.4 × 10 7 members for six randomized amino acids). For synthetic cyclic peptide libraries, there are several approaches for identification of hits, including mass spectrometry, or by sequencing an associated genetic tag (incorporated during library synthesis). 13For the purpose of this review, we have divided cyclic peptide libraries into three main categories: biologic, semisynthetic, and fully synthetic. Some of these libraries are constrained to the canonical peptidogenic amino acids, whereas others are able to include nonpeptidogenic amino acids such as β-or γ-amino acids, D-amino acids, or nonnatural amino acids. 14-16The majority of biologically produced cyclic peptide libraries are formed using phage/phagemid display 8,17 or by splitintein cyclisation of peptides and proteins (SICLOPPS). 11,18,19 The latter uses a selectively randomized library of splitinteins for the production of genetically encoded, backbone cyclized peptide libraries. Semisynthetic libraries are able to incorporate nonpeptidogenic amino acids while retaining ribosomal synthesis and an associated genetic tag. The most frequently used method for semisynthetic library production is mRNA display 7,20 ; novel variants thereof include random nonstandard peptide integrated discovery (RaPID) 14 or protein synthesis using recombinant elements (PURE).15 Both methods use promiscuous enzymes to expand the amino acid library encoded into peptides by reprogramming codons. 16Another semisynthetic technique has been used for the creation of macrocyclic organic-peptide hybrids (MOrPHs) 21,22 and bicyclic organo-peptide hybrids (BOrPHs), 23 which produce geometrically constrained peptide libraries. Fully AbstractThe identification of initial hits is a crucial stage in the drug discovery process. Although many projects adopt high-throughput screening of small-molecule libraries at this stage, there is significant potential for s...

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“…Moreover, the requirement for an N-terminal cysteine and a C-terminal thioester in NCL is not always compatible with Fmoc solid phase peptide synthesis or recombinant expression. Accordingly, a number of different approaches to backbone cyclization have been developed (29), including expressed protein ligation (33,34), intein-mediated protein trans-splicing (35), and genetic code reprogramming (36).…”

mentioning

confidence: 99%

Semienzymatic Cyclization of Disulfide-rich Peptides Using Sortase A

Jia

Kwon

Wang

et al. 2014

Journal of Biological Chemistry

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Background: Sortase A (SrtA) is a transpeptidase capable of catalyzing the formation of amide bonds. Results: SrtA was used to backbone-cyclize disulfide-rich peptides, including kalata B1, ␣-conotoxin Vc1.1, and SFTI-1. Conclusion: SrtA-mediated cyclization is applicable to small disulfide-rich peptides. Significance: SrtA-mediated cyclization is an alternative to native chemical ligation for the cyclization of small peptides of therapeutic interest.

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Diverse backbone-cyclized peptides via codon reprogramming

Cited by 149 publications

References 25 publications

Flexizymes-facilitated Genetic Code Reprogramming Leading to the Discovery of Drug-like Peptides

Flexizymes-facilitated Genetic Code Reprogramming Leading to the Discovery of Drug-like Peptides

Methods for the Creation of Cyclic Peptide Libraries for Use in Lead Discovery

Semienzymatic Cyclization of Disulfide-rich Peptides Using Sortase A

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