Design and synthesis of dye-conjugated hepsin inhibitors

Kyul Kim; Hongmok Kwon; Doyoung Choi; Taehyeong Lim; Il Minn; Sang Hyun Son; Youngjoo Byun

doi:10.1016/j.bioorg.2019.102990

Design and synthesis of dye-conjugated hepsin inhibitors

Kyul Kim, Hongmok Kwon, Doyoung Choi, Taehyeong Lim, Il Minn, Sang Hyun Son, Youngjoo Byun

School of Medicine

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel hepsin-targeted imaging probes by conjugating the hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong hepsin-inhibitory activities with K_i values of 21 and 22 nM, respectively. Compound 2 showed selective uptake and retention in hepsin-overexpressing cells. This is the first report of hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing hepsin-based imaging probes and be as a prototype molecule in the design of new hepsin inhibitors.

Original language	English (US)
Article number	102990
Journal	Bioorganic Chemistry
Volume	89
DOIs	https://doi.org/10.1016/j.bioorg.2019.102990
State	Published - Aug 2019

Keywords

BODIPY
Hepsin
Optical dye
SulfoCy7

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Drug Discovery
Organic Chemistry

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10.1016/j.bioorg.2019.102990

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title = "Design and synthesis of dye-conjugated hepsin inhibitors",

abstract = "Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel hepsin-targeted imaging probes by conjugating the hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong hepsin-inhibitory activities with Ki values of 21 and 22 nM, respectively. Compound 2 showed selective uptake and retention in hepsin-overexpressing cells. This is the first report of hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing hepsin-based imaging probes and be as a prototype molecule in the design of new hepsin inhibitors.",

keywords = "BODIPY, Hepsin, Optical dye, SulfoCy7",

author = "Kyul Kim and Hongmok Kwon and Doyoung Choi and Taehyeong Lim and Il Minn and Son, {Sang Hyun} and Youngjoo Byun",

note = "Funding Information: We acknowledge support from the National Research Foundation ( 2014R1A4A1007304 and 2017R1A2B4005036 to Y.B., and 2015R1D1A4A01016638 to S.-H.S) and from Ministry of Health & Welfare, Republic of Korea ( HI16C1827 to Y.B.). Funding Information: We acknowledge support from the National Research Foundation (2014R1A4A1007304 and 2017R1A2B4005036 to Y.B. and 2015R1D1A4A01016638 to S.-H.S) and from Ministry of Health & Welfare, Republic of Korea (HI16C1827 to Y.B.). Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = aug,

doi = "10.1016/j.bioorg.2019.102990",

language = "English (US)",

volume = "89",

journal = "Bioorganic Chemistry",

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AU - Kim, Kyul

AU - Kwon, Hongmok

AU - Choi, Doyoung

AU - Lim, Taehyeong

AU - Minn, Il

AU - Son, Sang Hyun

AU - Byun, Youngjoo

N1 - Funding Information: We acknowledge support from the National Research Foundation ( 2014R1A4A1007304 and 2017R1A2B4005036 to Y.B., and 2015R1D1A4A01016638 to S.-H.S) and from Ministry of Health & Welfare, Republic of Korea ( HI16C1827 to Y.B.). Funding Information: We acknowledge support from the National Research Foundation (2014R1A4A1007304 and 2017R1A2B4005036 to Y.B. and 2015R1D1A4A01016638 to S.-H.S) and from Ministry of Health & Welfare, Republic of Korea (HI16C1827 to Y.B.). Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/8

Y1 - 2019/8

N2 - Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel hepsin-targeted imaging probes by conjugating the hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong hepsin-inhibitory activities with Ki values of 21 and 22 nM, respectively. Compound 2 showed selective uptake and retention in hepsin-overexpressing cells. This is the first report of hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing hepsin-based imaging probes and be as a prototype molecule in the design of new hepsin inhibitors.

AB - Hepsin is a type II serine protease that is highly expressed in neoplastic prostate. It is an attractive biomarker for imaging metastatic prostate cancer because of its overexpression in advanced prostate cancer and the location of its active site on the cell surface. We designed and synthesized novel hepsin-targeted imaging probes by conjugating the hepsin-binding ligand with near-infrared (NIR) optical dyes. The Leu-Arg dipeptides, attached to BODIPY or SulfoCy7, exhibited strong hepsin-inhibitory activities with Ki values of 21 and 22 nM, respectively. Compound 2 showed selective uptake and retention in hepsin-overexpressing cells. This is the first report of hepsin-targeted optical probes with strong binding affinities and high selectivity over matriptase. Compound 2 has the potential to be used for developing hepsin-based imaging probes and be as a prototype molecule in the design of new hepsin inhibitors.

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Design and synthesis of dye-conjugated hepsin inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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