Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor

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Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold : Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor. / Xu, Peng; Xu, Mingming; Jiang, Longguang; Yang, Qinglan; Luo, Zhipu; Dauter, Zbigniew; Huang, Mingdong; Andreasen, Peter A.

I: Journal of Medicinal Chemistry, Bind 58, Nr. 22, 25.11.2015, s. 8868-8876.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Harvard

Xu, P, Xu, M, Jiang, L, Yang, Q, Luo, Z, Dauter, Z, Huang, M & Andreasen, PA 2015, 'Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor', Journal of Medicinal Chemistry, bind 58, nr. 22, s. 8868-8876. https://doi.org/10.1021/acs.jmedchem.5b01128

APA

Xu, P., Xu, M., Jiang, L., Yang, Q., Luo, Z., Dauter, Z., Huang, M., & Andreasen, P. A. (2015). Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor. Journal of Medicinal Chemistry, 58(22), 8868-8876. https://doi.org/10.1021/acs.jmedchem.5b01128

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MLA

Vancouver

Author

Xu, Peng ; Xu, Mingming ; Jiang, Longguang ; Yang, Qinglan ; Luo, Zhipu ; Dauter, Zbigniew ; Huang, Mingdong ; Andreasen, Peter A. / Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold : Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor. I: Journal of Medicinal Chemistry. 2015 ; Bind 58, Nr. 22. s. 8868-8876.

Bibtex

@article{1b91b6df70fc4c2e86ca5ffb82abc98a,
title = "Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold: Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor",
abstract = "All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.",
keywords = "MEDICINAL CHEMISTRY",
author = "Peng Xu and Mingming Xu and Longguang Jiang and Qinglan Yang and Zhipu Luo and Zbigniew Dauter and Mingdong Huang and Andreasen, {Peter A}",
year = "2015",
month = nov,
day = "25",
doi = "10.1021/acs.jmedchem.5b01128",
language = "English",
volume = "58",
pages = "8868--8876",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "22",

}

RIS

TY - JOUR

T1 - Design of Specific Serine Protease Inhibitors Based on a Versatile Peptide Scaffold

T2 - Conversion of a Urokinase Inhibitor to a Plasma Kallikrein Inhibitor

AU - Xu, Peng

AU - Xu, Mingming

AU - Jiang, Longguang

AU - Yang, Qinglan

AU - Luo, Zhipu

AU - Dauter, Zbigniew

AU - Huang, Mingdong

AU - Andreasen, Peter A

PY - 2015/11/25

Y1 - 2015/11/25

N2 - All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.

AB - All serine proteases hydrolyze peptide bonds by the same basic mechanism and have very similar active sites, in spite of the fact that individual proteases have different physiological functions. We here report a strategy for designing high-affinity and high-specificity serine protease inhibitors using a versatile peptide scaffold, a 10-mer peptide, mupain-1 (CPAYSRYLDC). Mupain-1 was previously reported as a specific inhibitor of murine urokinase-type plasminogen activator (Ki = 0.55 μM) without measurable affinity to plasma kallikrein (Ki > 1000 μM). On the basis of a structure-based rational design, we substituted five residues of mupain-1 and converted it to a potent plasma kallikrein inhibitor (Ki = 0.014 μM). X-ray crystal structure analysis showed that the new peptide was able to adapt a new set of enzyme surface interactions by a slightly changed backbone conformation. Thus, with an appropriate re-engineering, mupain-1 can be redesigned to specific inhibitors of other serine proteases.

KW - MEDICINAL CHEMISTRY

U2 - 10.1021/acs.jmedchem.5b01128

DO - 10.1021/acs.jmedchem.5b01128

M3 - Journal article

C2 - 26536069

VL - 58

SP - 8868

EP - 8876

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 22

ER -