Peptide‐ or Protein‐Cleaving Agents Based on Metal Complexes

Chei, Woo Suk; Suh, Junghun

doi:10.1002/9780470144428.ch2

Cited by 25 publications

(7 citation statements)

References 140 publications

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“…In accordance with mechanisms generally proposed for ester or peptide hydrolysis by metal complexes, , three mechanisms summarized in Scheme can be proposed for the proteolytic action of Cu(II)oxacyclen and Cu(II)cyclen. These mechanisms have the same rate expression.…”

supporting

confidence: 59%

“…A variety of organic reactions are catalyzed by metalloenzymes by using the metal ions as Lewis acid catalysts , …”

mentioning

confidence: 99%

“…When a metal ion acts as a catalyst in the hydrolysis of a peptide bond, the metal-bound hydroxide ion and the metal-bound water molecule as well as the metal ion itself play several catalytic roles . Various metal complexes promote hydrolysis of peptide bonds. ,− Some of them end up with complexes formed with the product fragments and/or manifest activity only at acidic pH values. To exploit the catalytic center of artificial metalloproteases, the metal complexes should be regenerated after peptide hydrolysis and should manifest considerable activity at neutral pH values.…”

mentioning

confidence: 99%

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Proteolytic Activity of Cu(II) Complex of 1-Oxa-4,7,10-triazacyclododecane

Jang

Suh

2008

Org. Lett.

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Proteolytic activity of the Cu(II) complex of 1-oxa-4,7,10-triazacyclododecane (oxacyclen) was compared with that of the Cu(II) complex of 1,4,7,10-tetraazacyclododecane by using albumin, gamma-globulin, and myoglobin as substrates. Values of kcat/Km were greater for Cu(II)oxacyclen by 40-80 times. The enhanced activity is attributed to the increased Lewis acidity of Cu(II) due to substitution of one nitrogen donor atom with oxygen.

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supporting

confidence: 59%

“…A variety of organic reactions are catalyzed by metalloenzymes by using the metal ions as Lewis acid catalysts , …”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Proteolytic Activity of Cu(II) Complex of 1-Oxa-4,7,10-triazacyclododecane

Jang

Suh

2008

Org. Lett.

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“…1,2,7,[11][12][13][14][15][16][17][18][19] The present study indicates that the target-selective artificial proteases may be especially effective for amyloidoses such as Alzheimer's disease, diabetes, Parkinson's disease, Huntington's disease, and mad cow's disease for which the conventional drugs targeting active sites of proteins cannot be designed.…”

mentioning

confidence: 99%

Cleavage Agents for α-Synuclein

Lee¹,

Yoo²,

Jeong³

et al. 2008

Bulletin of the Korean Chemical Society

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“…[1][2][3][4][5][6][7][8][9] In the conventional approaches to design drugs that regulate the activities of disease-related proteins such as enzymes, receptors, or ion channels, attempts are made to discover small molecules that bind to the active sites of the disease-related proteins with high selectivity and high affinity. One molecule of the conventional drug can control the activity of at most one molecule of the target protein.…”

mentioning

confidence: 99%

Kinetic Studies on Proteolysis by Co(III) Complex of Cyclen

Jang¹,

Suh

2008

Bulletin of the Korean Chemical Society

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As a new paradigm for drug design, we have proposed catalytic drugs based on target-selective peptide-cleaving catalysts. [1][2][3][4][5][6][7][8][9] In the conventional approaches to design drugs that regulate the activities of disease-related proteins such as enzymes, receptors, or ion channels, attempts are made to discover small molecules that bind to the active sites of the disease-related proteins with high selectivity and high affinity. One molecule of the conventional drug can control the activity of at most one molecule of the target protein.When the substrate of a target-selective artificial protease is a protein related to a disease, the artificial protease can cleave and inactivate the target protein acting as a catalytic drug.Peptide-cleaving catalytic drugs have several advantages in comparison with conventional drugs. First, the catalytic nature of peptide cleavage allows decreases in the amounts of the drug dose and the reduction of the side effects. Second, strong binding to the target is not required if the peptide cleavage is fast enough for the peptide-cleaving catalysts. Third, the peptide-cleaving catalysts can be obtained even for proteins or peptides lacking active sites.We have discovered the first target-selective artificial protease by cleaving the backbone of myoglobin by hydrolysis.3,4 In addition, we were able to design an artificial protease that selectively hydrolyzed the polypeptide backbone of peptide deformylase, 5 a bacterial enzyme regarded as an important target 10 for designing antibiotics. We also synthesized artificial proteases selective for oligomers of amyloid β-42 peptide, 9 the pathogenic species 11 for Alzheimer's disease. Moreover, we have reported catalysts for oxidative decarboxylation of N-terminal aspartate residues of oligopeptides such as angiotensin II 6 and melanin-concentration hormone, 7,8 which are targets for designing drugs for hypertension 12 and obesity, 13 respectively. As the catalytic center for the peptide-cleaving catalysts, we have exploited the Co(III) complex of cyclen (Co(III)-cyclen). Co(III)cyclen itself has some activity for hydrolytic cleavage of peptide bonds. The catalytic activity of Co(III)-cyclen is enhanced to a high level by connecting it to a binding site which recognizes the target protein or peptide. If the effective concentration of Co(III)cyclen toward a reaction site on the target is sufficiently high in the targetcatalyst complex, peptide cleavage occurs at a reasonably high rate.If the Co(III)cyclen moiety of a peptide-cleaving catalyst cleaves non-target proteins in vivo, the catalyst can cause serious side effects. To utilize peptide-cleaving catalysts as catalytic drugs, therefore, it is necessary to demonstrate that random attack of the catalysts at non-target proteins is negligible.The kinetic data for the hydrolysis of an amide (formylmorpholine) by Co(III)cyclen have been reported.14 The second-order rate constant for the reaction was estimated as 0.26 M −1 h −1 at 60 o C and pD 5.9. Unlike the amide molecule, prote...

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Peptide‐ or Protein‐Cleaving Agents Based on Metal Complexes

Cited by 25 publications

References 140 publications

Proteolytic Activity of Cu(II) Complex of 1-Oxa-4,7,10-triazacyclododecane

Proteolytic Activity of Cu(II) Complex of 1-Oxa-4,7,10-triazacyclododecane

Cleavage Agents for α-Synuclein

Kinetic Studies on Proteolysis by Co(III) Complex of Cyclen

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