Interlocking Disulfides in Circular Proteins: Toward Efficient Oxidative Folding of Cyclotides

Aboye, Teshome Leta; Clark, Richard J.; Burman, Robert; Roig, Marta Bajona; Craik, David J.; Göransson, Ulf

doi:10.1089/ars.2010.3112

Cited by 45 publications

(75 citation statements)

References 46 publications

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“…Therefore, extraction of cystine-knot peptides from plants is a common way to isolate the wild type sequences [74,[129][130][131].…”

Section: Recombinant Productionmentioning

confidence: 99%

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Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

Avrutina

2016

Advances in Experimental Medicine and Biology

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Peptides with the cystine-knot architecture, often termed knottins, are promising scaffolds for biomolecular engineering. These unique molecules combine diverse bioactivities with excellent structural, thermal, and proteolytical stability. Being different in the composition and structure of their amino acid backbone, knottins share the same core element, namely cystine knot, which is built by six cysteine residues forming three disulfides upon oxidative folding. This motif ensures a notably rigid framework that highly tolerates both rational and combinatorial changes in the primary structure. Being accessible through recombinant production and total chemical synthesis, cystine-knot miniproteins can be endowed with novel bioactivities by variation of surface-exposed loops and incorporation of non-natural elements within their non-conserved regions towards the generation of tailor-made peptidic compounds. In this chapter the topology of cystine-knot peptides, their synthesis and applications for diagnostics and therapy is discussed.

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“…Therefore, extraction of cystine-knot peptides from plants is a common way to isolate the wild type sequences [74,[129][130][131].…”

Section: Recombinant Productionmentioning

confidence: 99%

“…Significant efforts have been made to determine folding pathways and optimize oxidative folding conditions [129,131,[147][148][149][150][151][152][153][154].…”

Section: Oxidative Foldingmentioning

confidence: 99%

Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

Avrutina

2016

Advances in Experimental Medicine and Biology

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“…The cyclization of backbone occurs after the forming of a cyclic cystine knot in vivo [27], although chemical synthetic research shows that the cyclic backbone is preferred for the generation of cyclic cystine knot in vitro [28,29]. The cyclization of the backbone is catalyzed by asparaginyl endopeptidase (AEP) [30,31].…”

Section: Endopeptidase-catalyzed Cyclizationmentioning

confidence: 99%

Various mechanisms in cyclopeptide production from precursors synthesized independently of non-ribosomal peptide synthetases

Xu¹,

Li²,

Du³

et al. 2011

ABBS

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An increasing number of cyclopeptides have been discovered as products of ribosomal synthetic pathway. The biosynthetic study of these cyclopeptides has revealed interesting new mechanisms for cyclization. This review highlighted the recent discoveries in cyclization mechanisms for cyclopeptides synthesized independently of non-ribosomal peptide synthetases, including endopeptidase-catalyzed cyclization, intein-mediated cyclization, and peptide synthetase-catalyzed cyclization. This information may help to design hybrid ribosomal and non-ribosomal biosynthetic systems to produce novel cyclopeptides with various bioactivities.

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“…[26,27] Aw elld escribed example is MCoTI-II, a3 4-merh ead-to-tail cyclic trypsin inhibitor isolated from Momordica cochinchinensis. [28] Althoughs everal synthetic protocols for cyclotides are welle stablished, [29][30][31][32] efficient head-to-tail cyclization still remains ac hallenge,e specially at al arger scale.H owever, aC EPS approach for the synthesis of cyclotides bears great potential. Thel inearo pen chain (oc-) MCoTI-II precursorp eptide Cam-ester was assembled using standard Fmoc-SPPS ( Figure 4A).…”

mentioning

confidence: 99%

Omniligase‐1: A Powerful Tool for Peptide Head‐to‐Tail Cyclization

Schmidt

Toplak²,

Quaedflieg³

et al. 2017

Adv Synth Catal

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Strategies for the efficients ynthesis of peptide macrocyclesh ave been al ong-standing goal. In this paper, we demonstrate the use of the peptide ligase termedo mniligase-1 as av ersatile and broadly applicable enzymatic toolf or peptide cyclization. Severalh ead-to-tail (multi)cyclic peptides have been synthesized, including the cyclotide MCoTI-II. Cyclization ando xidative foldingo ft he cyclotide MCoTI-II were efficiently performed in ao ne-pot reactiono na1 -gram scale.T he native cyclotide was isolated andt he correct disulfide bonding pattern was confirmed by NMRs tructure determination. Furthermore,c ompatibility of chemo-enzymatic peptide synthesis( CEPS) using omniligase1w ith methods such as chemical ligation of peptides onto scaffolds( CLIPS)w as successfully demonstrated by synthesizing ak inase-inhibitor derived tricyclic peptide.O ur studies indicate that the minimal ring size for omniligase-1 mediated cyclization is 11 amino acids,w hereas the cyclization of peptides longer than 12 amino acids proceeds with remarkablee fficiency.I na ddition,s everal macrocycles containing non-peptidic backbones( e.g.,p olyethylene glycol), isopeptide bonds (aminoa cid sidechain attachment) as well as d-amino acids couldbe efficiently cyclized.Keywords: chemo-enzymatic peptide synthesis (CEPS);c yclic peptides; cyclization;c yclotide synthesis;c yclotides;e nzyme catalysis;h ead-to-tail cyclization; ligases;m acrocycles;o mniligase-1;p eptides Peptide macrocyclesr epresent an extremely diverse class of molecules that attracti ncreased attentiona s drug leads and prospective pharmaceuticals,w ith currently over 30 cyclic peptides registered or in clinical trials.[1-3] Togetherw ith linearp eptides, they fill the gap between small-molecule drugs (less than 500 Da) and biologics (over 5000 Da) andh avet he potential to address previously "undruggable" targets. Many cyclicp eptides are characterized by their unique structural and enhancedb iopharmaceutical properties,s uch as an improved metabolic stability due to ar educed sensitivity to proteolytic cleavage.T he increasing number of cyclic peptidesu sed as therapeutics is accompanied by the need for efficient andc osteffectiver outes that enable their synthesis on al arge scale.M oreover, efficients ynthesiso fl arge libraries of cyclic peptides (e.g.,f or screeningp urposes) or of cyclicp eptides containing non-canonical amino acids (e.g., d-o ru nnatural amino acids to increase stability and diversity) is of importance.H owever, efficient cyclization of peptidesu sing traditional synthetic methodsi ss till ac hallenge.[4] Classical coupling reagents are often used to cyclize side-chain protected peptides in anhydrous organic solvents.H owever, heavy dilution to prevent polymerization,r isk of epimerization and ap oors olubility of side-chain protected peptideslimitthis approach, especially for peptides longer than 20 amino acids.[5] Native chemical ligation (NCL) [6] is often used to cyclize unprotected peptides in aqueous solution. However, not all pep...

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Interlocking Disulfides in Circular Proteins: Toward Efficient Oxidative Folding of Cyclotides

Cited by 45 publications

References 46 publications

Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

Various mechanisms in cyclopeptide production from precursors synthesized independently of non-ribosomal peptide synthetases

Omniligase‐1: A Powerful Tool for Peptide Head‐to‐Tail Cyclization

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