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Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action

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Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator : Mode of Action. / Roodbeen, Renée; Paaske, Berit; Jiang, Longguang; Jensen, Jan Kristian; Christensen, Anni; Nielsen, Jakob T; Huang, Mingdong; Mulder, Frans A.A.; Nielsen, Niels Christian; Andreasen, Peter; Jensen, Knud Jørgen.

In: ChemBioChem, Vol. 14, No. 16, 02.10.2013, p. 2179–2188.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Roodbeen, R, Paaske, B, Jiang, L, Jensen, JK, Christensen, A, Nielsen, JT, Huang, M, Mulder, FAA, Nielsen, NC, Andreasen, P & Jensen, KJ 2013, 'Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action', ChemBioChem, vol. 14, no. 16, pp. 2179–2188. https://doi.org/10.1002/cbic.201300335

APA

Roodbeen, R., Paaske, B., Jiang, L., Jensen, J. K., Christensen, A., Nielsen, J. T., Huang, M., Mulder, F. A. A., Nielsen, N. C., Andreasen, P., & Jensen, K. J. (2013). Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action. ChemBioChem, 14(16), 2179–2188. https://doi.org/10.1002/cbic.201300335

CBE

Roodbeen R, Paaske B, Jiang L, Jensen JK, Christensen A, Nielsen JT, Huang M, Mulder FAA, Nielsen NC, Andreasen P, Jensen KJ. 2013. Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action. ChemBioChem. 14(16):2179–2188. https://doi.org/10.1002/cbic.201300335

MLA

Vancouver

Roodbeen R, Paaske B, Jiang L, Jensen JK, Christensen A, Nielsen JT et al. Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action. ChemBioChem. 2013 Oct 2;14(16):2179–2188. https://doi.org/10.1002/cbic.201300335

Author

Roodbeen, Renée ; Paaske, Berit ; Jiang, Longguang ; Jensen, Jan Kristian ; Christensen, Anni ; Nielsen, Jakob T ; Huang, Mingdong ; Mulder, Frans A.A. ; Nielsen, Niels Christian ; Andreasen, Peter ; Jensen, Knud Jørgen. / Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator : Mode of Action. In: ChemBioChem. 2013 ; Vol. 14, No. 16. pp. 2179–2188.

Bibtex

@article{257b674e65a24b8a8f34b0799d6bf759,
title = "Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator: Mode of Action",
abstract = "The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptide-based inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established monocyclic peptide, upain-2. It was successfully converted to a bicyclic peptide, without loss of inhibitory properties. The aim was to produce a peptide cyclised by an amide bond with an additional stabilising across-the-ring covalent bond. We expected this bicyclic peptide to exhibit a lower entropic burden upon binding. Two bicyclic peptides were synthesised with affinities similar to that of upain-2, and their binding energetics were evaluated by isothermal titration calorimetry. Indeed, compared to upain-2, the bicyclic peptides showed reduced loss of entropy upon binding to uPA. We also investigated the solution structures of the bicyclic peptide by NMR spectroscopy to map possible conformations. An X-ray structure of the bicyclic-peptide-uPA complex confirmed an interaction similar to that for the previous upain-1/upain-2-uPA complexes. These physical studies of the peptide-protease interactions will aid future designs of bicyclic peptide protease inhibitors.",
keywords = "cancer, isothermal titration calorimetry, NMR spectroscopy, peptide-protease interactions, X-ray structures",
author = "Ren{\'e}e Roodbeen and Berit Paaske and Longguang Jiang and Jensen, {Jan Kristian} and Anni Christensen and Nielsen, {Jakob T} and Mingdong Huang and Mulder, {Frans A.A.} and Nielsen, {Niels Christian} and Peter Andreasen and Jensen, {Knud J{\o}rgen}",
note = "Copyright {\textcopyright} 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",
year = "2013",
month = oct,
day = "2",
doi = "10.1002/cbic.201300335",
language = "English",
volume = "14",
pages = "2179–2188",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "16",

}

RIS

TY - JOUR

T1 - Bicyclic Peptide Inhibitor of Urokinase-Type Plasminogen Activator

T2 - Mode of Action

AU - Roodbeen, Renée

AU - Paaske, Berit

AU - Jiang, Longguang

AU - Jensen, Jan Kristian

AU - Christensen, Anni

AU - Nielsen, Jakob T

AU - Huang, Mingdong

AU - Mulder, Frans A.A.

AU - Nielsen, Niels Christian

AU - Andreasen, Peter

AU - Jensen, Knud Jørgen

N1 - Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2013/10/2

Y1 - 2013/10/2

N2 - The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptide-based inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established monocyclic peptide, upain-2. It was successfully converted to a bicyclic peptide, without loss of inhibitory properties. The aim was to produce a peptide cyclised by an amide bond with an additional stabilising across-the-ring covalent bond. We expected this bicyclic peptide to exhibit a lower entropic burden upon binding. Two bicyclic peptides were synthesised with affinities similar to that of upain-2, and their binding energetics were evaluated by isothermal titration calorimetry. Indeed, compared to upain-2, the bicyclic peptides showed reduced loss of entropy upon binding to uPA. We also investigated the solution structures of the bicyclic peptide by NMR spectroscopy to map possible conformations. An X-ray structure of the bicyclic-peptide-uPA complex confirmed an interaction similar to that for the previous upain-1/upain-2-uPA complexes. These physical studies of the peptide-protease interactions will aid future designs of bicyclic peptide protease inhibitors.

AB - The development of protease inhibitors for pharmacological intervention has taken a new turn with the use of peptide-based inhibitors. Here, we report the rational design of bicyclic peptide inhibitors of the serine protease urokinase-type plasminogen activator (uPA), based on the established monocyclic peptide, upain-2. It was successfully converted to a bicyclic peptide, without loss of inhibitory properties. The aim was to produce a peptide cyclised by an amide bond with an additional stabilising across-the-ring covalent bond. We expected this bicyclic peptide to exhibit a lower entropic burden upon binding. Two bicyclic peptides were synthesised with affinities similar to that of upain-2, and their binding energetics were evaluated by isothermal titration calorimetry. Indeed, compared to upain-2, the bicyclic peptides showed reduced loss of entropy upon binding to uPA. We also investigated the solution structures of the bicyclic peptide by NMR spectroscopy to map possible conformations. An X-ray structure of the bicyclic-peptide-uPA complex confirmed an interaction similar to that for the previous upain-1/upain-2-uPA complexes. These physical studies of the peptide-protease interactions will aid future designs of bicyclic peptide protease inhibitors.

KW - cancer

KW - isothermal titration calorimetry

KW - NMR spectroscopy

KW - peptide-protease interactions

KW - X-ray structures

U2 - 10.1002/cbic.201300335

DO - 10.1002/cbic.201300335

M3 - Journal article

C2 - 24115455

VL - 14

SP - 2179

EP - 2188

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 16

ER -