In Vivo Imaging of Mouse Tumors by a Lipidated Cathepsin S Substrate

Hu, Hai; Vats, Divya; Vizovišek, Matej; Kramer, Lovro; Germanier, Catherine; Wendt, K. Ulrich; Rudin, Markus; Turk, Boris; Plettenburg, Oliver; Schultz, Carsten

doi:10.1002/anie.201310979

Cited by 53 publications

(52 citation statements)

References 23 publications

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“…The study demonstrates strong visualisation of the tumour site in vivo with very little noise generated as a result of substrate deposition in off-target tissues. Furthermore, signal was rapidly produced within 30 min, which increased steadily over the following 6 h before diminishing 24 h post-injection (Hu et al, 2014).…”

Section: Accurately Determining Cathepsin S Activitymentioning

confidence: 95%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

161

139

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Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain. Unsurprisingly, mis-regulation has implicated cathepsin S in a variety of pathological processes including arthritis, cancer, and cardiovascular disease, where it becomes secreted and can act on extracellular substrates. In comparison to many other cysteine cathepsin family members, cathepsin S has uniquely restricted tissue expression and is more stable at a neutral pH, which supports its involvement and importance in localised disease microenvironments. In this review, we examine the known involvement of cathepsin S in disease, particularly with respect to recent work indicating its role in mediating pain, diabetes, and cystic fibrosis. We provide an overview of current literature with regards cathepsin S as a therapeutic target, as well as its role and potential as a predictive diagnostic and/or prognostic marker in these diseases.

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Section: Accurately Determining Cathepsin S Activitymentioning

confidence: 95%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

161

139

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“…[7,8] Protein profiling with activity-basedp robesh as emergeda s ap owerful strategy to study enzyme functions and activities in complex proteomes. [20,21,[33][34][35] The visualization of the target is restricted to the activeform of the enzyme, which is of particular importance,b ecause enzyme expression levels do not alwaysc orrelate with the activity or the activity might be regulated post-translationally. [34,36] These probes consist of three essentialc omponents: ar eactive group, ar ecognition element, and ar eporter tag.…”

Section: Introductionmentioning

confidence: 99%

“…[20,21,[33][34][35] The visualization of the target is restricted to the activeform of the enzyme, which is of particular importance,b ecause enzyme expression levels do not alwaysc orrelate with the activity or the activity might be regulated post-translationally. [34,36] These probes consist of three essentialc omponents: ar eactive group, ar ecognition element, and ar eporter tag. The reactive group, as o-called warhead, leads to ac ovalent attachment to an active-site nucleophile.…”

Section: Introductionmentioning

confidence: 99%

Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity‐Based Probes of Matriptase‐2

Häußler

Mangold

Furtmann

et al. 2016

Chemistry A European J

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Matriptase-2, a type II transmembrane serine protease, plays a key role in human iron homeostasis. Inhibition of matriptase-2 is considered as an attractive strategy for the treatment of iron-overload diseases, such as hemochromatosis and β-thalassemia. In the present study, synthetic routes to nine dipeptidomimetic inactivators were developed. Five active compounds (41-45) were identified and characterized kinetically as irreversible inhibitors of matriptase-2. In addition to a phosphonate warhead, these dipeptides possess two benzguanidine moieties as arginine mimetics to provide affinity for matriptase-2 by binding to the S1 and S3/S4 subpockets, respectively. This binding mode was strongly supported by covalent docking analysis. Compounds 41-45 were obtained as mixtures of two diastereomers and were therefore separated into the single epimers. Compound 45 A, with S configuration at the N-terminal amino acid and R configuration at the phosphonate carbon atom, was the most potent matriptase-2 inactivator with a rate constant of inactivation of 2790 m(-1) s(-1) and abolished the activity of membrane-bound matriptase-2 on the surface of intact cells. Based on the chemotyp of phosphono bisbenzguanidines, the design and synthesis of a fluorescent probe (51 A) by insertion of a coumarin label is described. The in-gel fluorescence detection of matriptase-2 was demonstrated by applying 51 A as the first activity-based probe for this enzyme.

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“…In another example of protease substrates, Turk et al designed probes based on the structures of highly selective inhibitors by converting them into substrates of specific cathepsin proteases (Hu, et al, 2014; Watzke, et al, 2008). Using this ‘reverse-design’ approach, they engineered a substrate-based probe that is highly selective for cathepsin S (Link and Zipfel, 2006).…”

Section: Substrate and Activity-based Probesmentioning

confidence: 99%

“…The probe was designed from a non-peptidic, high affinity inhibitor to control selectivity and benefit from the optimized in vivo properties of the drug scaffold. These substrate probes produce a high signal in transplanted tumors in a short timeframe, generating signal as soon as 30 minutes after probe injection (Hu, et al, 2014). …”

Section: Substrate and Activity-based Probesmentioning

confidence: 99%

A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application

Garland

Yim

Bogyo

2016

Cell Chemical Biology

209

188

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The Precision Medicine Initiative aims to use advances in basic and clinical research to develop therapeutics that selectively target and kill cancer cells. Under the same doctrine of precision medicine, there is an equally important need to visualize these diseased cells to enable diagnosis, facilitate surgical resection and monitor therapeutic response. Therefore, there is a great opportunity for chemists to develop chemically tractable probes that can image cancer in vivo. This review focuses on recent advances in the development of optical probes as well as their current and future applications in the clinical management of cancer. The progress in probe development described here suggests that optical imaging is an important and rapidly developing field of study that encourages continued collaboration between chemists, biologists and clinicians to further refine these tools for interventional surgical imaging, as well as for diagnostic and therapeutic applications.

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In Vivo Imaging of Mouse Tumors by a Lipidated Cathepsin S Substrate

Cited by 53 publications

References 23 publications

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Phosphono Bisbenzguanidines as Irreversible Dipeptidomimetic Inhibitors and Activity‐Based Probes of Matriptase‐2

A Bright Future for Precision Medicine: Advances in Fluorescent Chemical Probe Design and Their Clinical Application

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