Enzyme-catalyzed peptide cyclization

Schmidt, Marcel; Toplak, Ana; Quaedflieg, Peter J. L. M.; Maarseveen, Jan H. van; Nuijens, Timo

doi:10.1016/j.ddtec.2017.11.007

Cited by 47 publications

(47 citation statements)

References 53 publications

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“…Besides the naturally occurring enzymes, some modified enzymes have also been developed, such as peptiligase . Compared with Srt A and butelase 1, peptiligase has more flexible recognition site and higher catalytic molar efficiency ( < 0.0003 molar equivalency) . However, the requirement of a C ‐terminal ester group extremely restricts its application in pharmaceutical industries.…”

Section: Strategies To Develop Cyclic Peptides Into Therapeutic Agentsmentioning

confidence: 99%

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Jing

Jin

2019

Medicinal Research Reviews

121

130

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As a versatile therapeutic modality, peptides attract much attention because of their great binding affinity, low toxicity, and the capability of targeting traditionally “undruggable” protein surfaces. However, the deficiency of cell permeability and metabolic stability always limits the success of in vitro bioactive peptides as drug candidates. Peptide macrocyclization is one of the most established strategies to overcome these limitations. Over the past decades, more than 40 cyclic peptide drugs have been clinically approved, the vast majority of which are derived from natural products. The de novo discovered cyclic peptides on the basis of rational design and in vitro evolution, have also enabled the binding with targets for which nature provides no solutions. The current review summarizes different classes of cyclic peptides with diverse biological activities, and presents an overview of various approaches to develop cyclic peptide‐based drug candidates, drawing upon series of examples to illustrate each strategy.

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Section: Strategies To Develop Cyclic Peptides Into Therapeutic Agentsmentioning

confidence: 99%

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Jing

Jin

2019

Medicinal Research Reviews

121

130

View full text Add to dashboard Cite

show abstract

“…48 In the context of cyclization of short peptides, transglutaminase has been utilized either alone or in combination with orthogonal cyclization agents to construct cyclic and polycyclic constructs comprising 6 -12 residues. 37,49 Considerable efforts have been dedicated to the engineering of the enzyme, 50 the identification of its recognition sequence, and the optimization of the reaction conditions to increase the yield of ligation; 37,51 in particular, it has been recognized that appending the N-terminal dipeptide Ala-Leu significantly increases the cyclization yield. 37 In this study, we referred to the sequence ALQSGSRGGGKS as linear precursor to evaluate the efficiency of cyclization on the surface of yeast cells; this peptide, in fact, served as model substrate in prior work on transglutaminase-mediated cyclization.…”

Section: Evaluation Of Extracellular Transglutaminase-mediated Peptidmentioning

confidence: 99%

Screening of yeast display libraries of enzymatically-cyclized peptides to discover macrocyclic peptide ligands

Bowen

Schneible

Labar

et al. 2020

Preprint

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Abstract. We present the construction and screening of yeast display libraries of cyclic peptides wherein site-selective enzymatic cyclization of linear peptides is achieved using bacterial transglutaminase. To this end, we developed two alternative routes, namely (i) yeast display of linear peptides followed by treatment with recombinant transglutaminase in solution; or (ii) intracellular co-expression of linear peptides and transglutaminase to achieve cyclization in the endoplasmic reticulum prior to yeast surface display. The cyclization yield was evaluated via orthogonal detection of epitope tags integrated in the yeast-displayed peptides by flow cytometry, and via comparative cleavage of cyclic vs. linear peptides by tobacco etch virus (TEV) protease. Subsequently, yeast display libraries of transglutaminase-cyclized peptides were screened to isolate binders to the N-terminal region of the Yes-Associated Protein (YAP) and its WW domains using magnetic selection and fluorescence activated cell sorting (FACS). The identified cyclic peptide cyclo[E-LYLAYPAH-K] featured a KD of 1.67 μM for YAP and 0.84 μM for WW as well as high binding selectivity against albumin and lysozyme. These results demonstrate the usefulness of yeast surface display for screening transglutaminase-cyclized peptide libraries, and efficient identification of cyclic peptide ligands.

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“…Amide bond formation is one of the most used methods to achieve peptide cyclization. This strategy was employed to reduce the N-terminal and C-terminal proportion and lower the ligands' susceptibility to biological degradation (Schmidt et al 2017). From this step, only 22 peptide ligands were eligible to be subjected to the second series of docking simulation due to the structural compatibility (the ability of peptide to cyclized).…”

Section: Cyclization Of Potential Peptide Ligandsmentioning

confidence: 99%

Identification of Novel Peptides Targeting DNA Methyltransferase 1 (DNMT-1) for Breast Cancer Treatment

Saragih

Stephanie

Alkaff

et al. 2020

Rev. Bras. Farmacogn.

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Epigenetic alteration shows an essential role in the process of breast cancer cell proliferation and propagation. DNA methyltransferase (DNMT) is responsible for DNA methylation, resulted in the epigenetic silencing of multiple genes. Hence, inhibiting DNMT-1 is a promising way to block uncontrolled DNA methylation. This study aimed to retrieve a potential peptide compound as DNMT-1 inhibitor due to its desirable properties as drug candidate through virtual screening and molecular docking simulation. A total of 51,957 peptide ligands from PubChem database underwent computational pharmacological screening to eliminate compounds with undesired characteristics. Molecular docking simulation was done with generated pharmacophore features, and the potential ligands with good ΔG binding, RMSD value, and molecular interaction were cyclized to increase the bioavailability of the peptides. Cyclic peptide ligands were tested for its interaction with DNMT-1 protein and ADME-Tox properties. From these steps, three cyclic peptide ligands showed desirable characteristics as a new drug candidate for the DNMT1 inhibitor.

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Enzyme-catalyzed peptide cyclization

Cited by 47 publications

References 53 publications

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

Screening of yeast display libraries of enzymatically-cyclized peptides to discover macrocyclic peptide ligands

Identification of Novel Peptides Targeting DNA Methyltransferase 1 (DNMT-1) for Breast Cancer Treatment

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