Through the looking glass: milestones on the road towards mirroring life

Rohden, Fabian; Hoheisel, Jörg D.; Wieden, Hans-Joachim

doi:10.1016/j.tibs.2021.06.006

Cited by 9 publications

(4 citation statements)

References 93 publications

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“…The genome of the laboratory strain E. coli K12 encodes for approximately 4300 proteins, [21] but only a small fraction of their enantiomeric counterparts have been reported. [22] Many of these proteins bear intrinsic synthetic challenges, because of their size, post‐translational modifications and folding (see section 3). Construction of the necessary mirror‐image oligonucleotides is also a major challenge.…”

Section: Research Surrounding D‐protein Enantiomersmentioning

confidence: 99%

D‐Peptide and D‐Protein Technology: Recent Advances, Challenges, and Opportunities**

2022

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Total chemical protein synthesis provides access to entire Dprotein enantiomers enabling unique applications in molecular biology, structural biology, and bioactive compound discovery. Key enzymes involved in the central dogma of molecular biology have been prepared in their D-enantiomeric forms facilitating the development of mirror-image life. Crystallization of a racemic mixture of L-and D-protein enantiomers provides access to high-resolution X-ray structures of polypeptides. Additionally, D-enantiomers of protein drug targets can be used in mirror-image phage display allowing discovery of nonproteolytic D-peptide ligands as lead candidates. This review discusses the unique applications of D-proteins including the synthetic challenges and opportunities.

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Section: Research Surrounding D‐protein Enantiomersmentioning

confidence: 99%

D‐Peptide and D‐Protein Technology: Recent Advances, Challenges, and Opportunities**

2022

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“…To date, several inhibitors have been identified by mirror-image screening for therapeutic targets, including vascular endothelial growth factor, , amyloid β, and human immunodeficiency virus envelope protein . Additionally, mirror-image forms of TNF, Kirsten rat sarcoma viral oncogene homologue (G12 V), and other attractive therapeutic targets have been chemically synthesized for use as target proteins in mirror-image screening. In this study, we describe the chemical synthesis of a mirror-image protein of IL-6 for subsequent use in mirror-image screening.…”

Section: Introductionmentioning

confidence: 99%

Chemical Synthesis of Interleukin-6 for Mirror-Image Screening

Aoki,

Maeda,

Inuki

et al. 2024

Bioconjugate Chem.

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, a multifunctional cytokine, is an attractive therapeutic target for immunological and inflammatory diseases. We investigated the chemical synthesis of IL-6 and its enantiomer (D-IL-6) using a sequential N-to-C native chemical ligation strategy from six peptide segments. Solubilizing Trt-K 10 tags improved the intermediate solubility and served as protecting groups during the metal-free desulfurization to facilitate the synthesis of full-length IL-6 protein. Synthetic L-IL-6 and recombinant IL-6 exhibited nearly identical structural and binding properties. The symmetrical binding property of D-IL-6 was also demonstrated by functional analysis using IL-6-binding peptides. The resulting functional D-IL-6 was employed to screen a phagedisplayed antibody fragment library, leading to the identification of several D-IL-6-binding single-domain antibodies. This work will contribute to the development of novel, potent IL-6 inhibitors without the adverse effects of undesired immune activation.

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“…10 There are many peptide synthesis methods, and solid phase peptide synthesis (SPPS) is the most commonly used peptide synthesis method. 11 The two most widely used N(α)protecting groups in SPPS are 9-fluorenylmethyloxycarbonyl (Fmoc) and tert-butyl carbonyl (Boc), and the Fmoc method requires a milder environment. 12 Here, we synthesized a pentapeptide peptide library with an antibacterial effect by the Fmoc method and screened the peptide chain with an antibacterial effect by cell membrane chromatography.…”

Section: Introductionmentioning

confidence: 99%

“…There are many peptide synthesis methods, and solid phase peptide synthesis (SPPS) is the most commonly used peptide synthesis method. 11 The two most widely used N(α)-protecting groups in SPPS are 9-fluorenylmethyloxycarbonyl (Fmoc) and tert -butyl carbonyl (Boc), and the Fmoc method requires a milder environment. 12…”

Section: Introductionmentioning

confidence: 99%