Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity

Meinander, Kristian; Weisell, Janne; Pakkala, Miikka; Tadd, Andrew C.; Hekim, Can; Kallionpää, Roope A.; Widell, Kim; Stenman, Ulf‐Håkan; Koistinen, Hannu; Närvänen, Ale; Vepsäläinen, Jouko; Luthman, Kristina; Wallén, Erik A.A.

doi:10.1039/c3md20292e

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…This may be caused by the short halflife of the peptides caused by rapid renal excretion and breakdown in plasma by exopeptidases. Therefore, more stable peptide analogs and synthetic peptidomimetics are being developed, in which part of the peptide structure is replaced by building blocks that are resistant to proteolytic breakdown 205,206 . Recently, the first small drug-like molecule Figure 8.…”

Section: Development Of Peptides Modulating the Proteolytic Activity mentioning

confidence: 99%

Biomarker development, from bench to bedside

Stenman

2015

Critical Reviews in Clinical Laboratory Sciences

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Application of laser & photonics in dentistry and medicine has a long history, however, it is still emerging as a new field enabling the application of advanced technology at precise size and levels and the exploitation of novel properties. Many areas of dental/medical device are expected to benefit from photonics including sensors for use in the laboratory , the clinic, and within the human body. For example, the potential uses of laser include the early detection and treatment of disease. These new innovative biomedical pho-tonics include "advanced bioimaging" to push photon-based imaging tools to new limits of resolution and utility for "molecular and cellular imaging" to develop and apply advanced optical diagnostic probes to important problems in molecular and cellular biology, and "biomedical photon-ics" to translate photonics to clinical dentistry/medicine for disease screening, diagnosis and therapy. Launched in April 2015, the Japan Agency for Medical Research and Development （AMED） pursues its assigned mission to fast-track medical research and development in support of humanity. AMED is currently tackling the challenge of reforming Japan＇s funding allocation and evaluation systems. Other significant tasks in fast-tracking the social implementation of research outcomes include rapid diagnosis of undiagnosed diseases, and novel therapeutic interventions for patients. AMED engages in research and development in the field of medicine, establishing and maintaining an environment for this R&D, and providing funding, in order to promote integrated medical R&D from basic research to practical applications, to smoothly achieve application of outcomes, and to achieve comprehensive and effective establishment / maintenance of an environment for medical R&D. Providing a one-stop service for research expenses, AMED consolidates budgets for research expenses, which had previously been allocated from different sources-the Ministry of Education, Culture, Sports, Science and Technology , the Ministry of Health, Labour and Welfare, and the Ministry of Economy, Trade and Industry. AMED aims to achieve the world＇s highest level of medical care / service and to form a society in which people live long, healthy lives by promoting integrated research and development, from basic research to practical application, and by establishing and maintaining an environment therefor, and linking this to various forms of growth in medical R&D. In this special lecture I would introduce a birds-eye view not only AMED supporting R&D program but also FMDIPA activity to develop dental/medical laser device industry, currently being undertaken to overcome the problems facing dental/medical diseases. He has made extensive contributions to the development of the bioengineering profession worldwide through his extensive professional activities and service with the government. He has also extensive experience in working with industry partners. In recognition of his contribution and leadership, he was elected for the initiative member to start up t...

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Section: Development Of Peptides Modulating the Proteolytic Activity mentioning

confidence: 99%

Biomarker development, from bench to bedside

Stenman

2015

Critical Reviews in Clinical Laboratory Sciences

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“…As the terminal NH 2 group does not seem to be critical for biological activity, analogues 3c and 3d were also included in the series. Replacing the disulfide bridge with a hydrocarbon linker has been reported to considerably increase the in vivo stability and bioavailability of peptides. , A similar alkene linker has already been shown to be a successful disulfide bridge replacement in the other KLK3-stimulating peptide, C-4 . However, in the C-4 peptide, the alkene linker was introduced after the peptide synthesis using a ring-closing metathesis reaction that gave an inseparable mixture of the E - and Z -alkenes.…”

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“…To verify the stereochemistry of the double bond in the purified pseudopeptide 3c , we also analyzed it by NMR using a method we have utilized in a previous study . This showed that the peptide exclusively contained the E- isomer.…”

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“…16,17 A similar alkene linker has already been shown to be a successful disulfide bridge replacement in the other KLK3-stimulating peptide, C-4. 18 However, in the C-4 peptide, the alkene linker was introduced after the peptide synthesis using a ring-closing metathesis reaction that gave an inseparable mixture of the Eand Zalkenes.…”

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“…In this work, we have presented the replacement of a terminal disulfide bridge using an orthogonally protected building block. Together with the pseudopeptides of the KLK3-stimulating peptide C-4, which we have published previously, 18 we have now successfully introduced similar hydrocarbon-based disulfide bridge replacements in two structurally different KLK3-stimulating pseudopeptides. Notably, pseudopeptides 3a−3d have been synthesized employing a synthetic strategy different from that used for pseudopeptides based on C-4.…”

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Replacement of the Disulfide Bridge in a KLK3-Stimulating Peptide Using Orthogonally Protected Building Blocks

Meinander

Pakkala

Weisell

et al. 2013

ACS Med. Chem. Lett.

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Peptide "B-2", which is one of the most potent kallikrein-related peptidase 3 (KLK3)-stimulating compounds, consists of 12 amino acids and is cyclized by a disulfide bridge between the N- and C-terminal cysteines. Orthogonally protected building blocks were used in the peptide synthesis to introduce a disulfide bridge mimetic consisting of four carbon atoms. The resulting pseudopeptides with alkane and E-alkene linkers doubled the proteolytic activity of KLK3 at a concentration of 14 μM. They were almost as potent as the parent "B-2" peptide, which gives a 3.6-fold increase in the proteolytic activity of KLK3 at the same concentration.

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The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2013

Herndon

2015

Coordination Chemistry Reviews

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Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity

Abstract: First successful pseudopeptides of the KLK3-activating bicyclic peptide “C-4” are reported.

Cited by 6 publications

References 22 publications

Biomarker development, from bench to bedside

Biomarker development, from bench to bedside

Replacement of the Disulfide Bridge in a KLK3-Stimulating Peptide Using Orthogonally Protected Building Blocks

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2013

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