Target-selective peptide-cleaving catalysts as a new paradigm in drug design

Lee, Tae Yeon; Suh, Junghun

doi:10.1039/b710345j

Cited by 56 publications

(39 citation statements)

References 54 publications

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“…At present, target selectivity is realized by the ligand-assisted direction of chemically reactive molecules (chemical modifiers) 1, [3][4][5][6][7][8] . Target selectivity in this approach relies on proximity effects.…”

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confidence: 99%

Switchable photooxygenation catalysts that sense higher-order amyloid structures

et al. 2016

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Proteins can misfold into amyloid structures that are associated with diseases; however, the same proteins often have important biological roles. To degrade selectively the amyloid form without affecting the fraction of functional protein is, therefore, an attractive goal. Here we report target-state-dependent photooxygenation catalysts that are active only when bound to the cross-β-sheet structure that is characteristic of pathogenic aggregated amyloid proteins. We show these catalysts can selectively oxygenate the amyloid form of amyloid β-protein (Aβ) 1-42 in the presence of non-amyloid off-target substrates. Furthermore, photooxygenation with a catalyst that bears an Aβ-binding peptide attenuated the Aβ pathogenicity in the presence of cells. We also show that selective photooxygenation is generally applicable to other amyloidogenic proteins (amylin, insulin, β2-microglobulin, transthyretin and α-synuclein) and does not affect the physiologically functional non-aggregate states of these proteins. This is the first report of an artificial catalyst that can be selectively and reversibly turned on and off depending on the structure and aggregation state of the substrate protein.

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confidence: 99%

Switchable photooxygenation catalysts that sense higher-order amyloid structures

et al. 2016

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“…Moreover, target‐selective peptide catalysts are emerging as a potential alternative to conventional drugs. They are required in tiny amounts and they may be identified without information about the target protein . In this perspective, protein‐cleaving drugs would be particularly advantageous.…”

Section: Figurementioning

confidence: 99%

“…[3] Moreover,t arget-selective peptide catalysts are emerging as ap otential alternative to conventional drugs.T hey are requiredi nt iny amountsa nd they may be identified without information about the targetp rotein. [4] In [a] A. [b] L. P. W. M. Lelieveldt + Current address:Department of Biomolecular Chemistry Radboud UniversityN ijmegen,H eyendaalseweg 135 6525 AJ Nijmegen (The Netherlands) [ + + ] These authors contributed equally to this work.Supporting information, which includes detailed description of the synthetic procedures, LC-MS chromatograms, and 1 Ha nd 13 CNMR and HRMS analysis, and the ORCID identification number(s)f or the author(s) of this article can be foundu nder: https://doi.…”

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confidence: 99%

“…-P-V-F-H-K''-G-OH4 14Bpy-2 Cu + 28 Y'flW-S-T-R-K-K''-G-OH 5 14 Bpy-2 Cu + 29 Y'-KflL-R-A-F-K''-G-OH 6 14 Bpy-2 Cu + 30 Y'-R-MflL-Q-K-K''-G-OH 7 Fe 2 + 31 Y'flF-R-Y-D-H-K''-G-OH 8 20 Phen-4 Cu + 32 Y'-H-K-A-RflR-K''-G-OH 920Phen-4 Cu+ 33 Y'-L-S-KflK-A-K''-G-OH 10 21 Phen-4 Fe 2 + 34 Y'-AflQ-T-L-L-K''-G-OH 11 Fe 2 + 35 Y'-Q-L-R-LflH-K''-G-OH Molecular modeling presenting the tetrahedral intermediate of substrate 34, Y'-AflQ-T-L-L-K''-G-OH tightlybound to catalyst 22.…”

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Metallo‐Organozymes with Specific Proteolytic Activity

Embaby

Lelieveldt

Diness

et al. 2018

Chemistry A European J

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Metallopeptides that show efficiency and selectivity in peptide bond cleavage in water at room temperature and neutral conditions are presented. These small and versatile organozymes take advantage of metal-coordinating building blocks that are strategically positioned centrally in a peptide backbone or in a peptide macrocycle. This approach provided peptide-metal complexes with scaffolds capable of utilizing the peptide functionality for productive binding of fluorogenic FRET peptide substrates, subsequently leading to highly selective peptide bond cleavage. The ligand chemistry has been optimized to provide an easy access to new metallo-peptides with the ability to cleave previously inaccessible peptide bonds. Evolutionary principles of stepwise selection and variation offered by combinatorial methods were used and were guided by molecular modeling to develop catalytic metallo-peptides that mimic metalloproteases.

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“…[4] We have been interested in designing artificial proteases because of the high stability [5] of peptide bonds as well as the importance of oligopeptides and proteins in modern biology. [6][7][8] Furthermore, proteases are commercially the most important enzymes. In this Focus Review, various attempts made by several scientists to synthesize effective artificial proteases are summarized together with our attempts to provide a new therapeutic option for amyloid diseases with artificial proteases.…”

Section: Introductionmentioning

confidence: 99%

Progress in Designing Artificial Proteases: A New Therapeutic Option for Amyloid Diseases

Suh

2013

Asian J Org Chem

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This Focus Review describes the evolution of artificial proteases, which are synthetic catalysts for peptide hydrolysis that mimic the action of natural proteases. The evolution took place through discovery of catalytic centers for peptide hydrolysis, attachment of substrate‐recognition sites to the catalytic centers, and the advent of target‐selective artificial proteases. Application of the target‐selective artificial proteases led to a therapeutic option for amyloid diseases, such as Alzheimer’s disease and diabetes.

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Target-selective peptide-cleaving catalysts as a new paradigm in drug design

Cited by 56 publications

References 54 publications

Switchable photooxygenation catalysts that sense higher-order amyloid structures

Switchable photooxygenation catalysts that sense higher-order amyloid structures

Metallo‐Organozymes with Specific Proteolytic Activity

Progress in Designing Artificial Proteases: A New Therapeutic Option for Amyloid Diseases

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