Prodrug-Inspired Probes Selective to Cathepsin B over Other Cysteine Cathepsins

Chowdhury, Mosharaf; Moya, I.A.; Bhilocha, Shardul; McMillan, Cody C.; Vigliarolo, Brady G.; Zehbe, Ingeborg; Phenix, Christopher P.

doi:10.1021/jm500544p

Cited by 43 publications

(30 citation statements)

References 45 publications

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“…Cathepsin B-specific module, for example, has been successfully implemented for this role, which led to the development of FDA approved therapies; for example, Brentuximab vedotin (Adcetris ® ) for CD30-positive relapsed or refractory Hodgkin s lymphoma. In addition, protease cleavable prodrug strategy has also inspired the development of cathepsin B selective probe and even enabled real-time monitoring of drug release [182,183]. Interestingly, Ueki et al slightly maneuvered this approach to acquire a prodrug which gets serially activated by histone deacetylase (HDAC) and cathepsin L, and subsequently delivers the cytotoxic payload, puromycin, to cancer cells [184].…”

Section: Final Perspectivesmentioning

confidence: 99%

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Dana

Pathak

2020

Molecules

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Human cathepsin L belongs to the cathepsin family of proteolytic enzymes with primarily an endopeptidase activity. Although its primary functions were originally thought to be only of a housekeeping enzyme that degraded intracellular and endocytosed proteins in lysosome, numerous recent studies suggest that it plays many critical and specific roles in diverse cellular settings. Not surprisingly, the dysregulated function of cathepsin L has manifested itself in several human diseases, making it an attractive target for drug development. Unfortunately, several redundant and isoform-specific functions have recently emerged, adding complexities to the drug discovery process. To address this, a series of chemical biology tools have been developed that helped define cathepsin L biology with exquisite precision in specific cellular contexts. This review elaborates on the recently developed small molecule inhibitors and probes of human cathepsin L, outlining their mechanisms of action, and describing their potential utilities in dissecting unknown function.Molecules 2020, 25, 698 2 of 41 also now well established and has been a subject of elegant reviews elsewhere [25][26][27]. Unfortunately, several overlapping and redundant functions of cathepsin L have also emerged [5,[28][29][30]. It is therefore critically important that its functional biology in both normal and disease-specific cell types be clearly annotated before significant resources are directed in drug discovery endeavors. In this review, we will briefly outline the biogenesis of cathepsin L, describe its post-translational processing and trafficking, and highlight key structural features required for formation of an active and mature cathepsin L. A brief summary of cathepsin L biology and its role in human diseases is provided next. Finally, a detailed and up-to-date report on existing cathepsin L-targeting small molecule inhibitors and functional probes with their mechanistic details is described.Human cathepsin L gene, CTHL (Uniprot primary accession number: P07711), located at the 9q21-q22 position of chromosome 9, encodes for a total of 333 amino acid peptide sequence (M.W. = 37,564 kDa) [31]. The coding space includes the regions of a N-terminal signal peptide, two pro-peptides, and two mature peptides comprising of a heavy (H) chain and a light (L) chain ( Figure 1). After transcription, the signal peptide is co-translationally removed in polysome and the resulting 41 kDa pro-cathepsin L is translocated to endoplasmic reticulum where it undergoes N-linked glycosylation with mannose rich sugars. The mannose sugars on the pro-cathepsin L are then phosphorylated in cis Golgi by UDP-N-acetylglucosamine:N-acetylglucosaminephosphotransferase enzyme [32]. The mannose-6-phosphate (M6P) receptors located on the surface of the trans Golgi network recognize the M6P-pro-cathepsin peptide and deliver the pro-cathepsin L peptide to the lysosome via the endolysosomal pathway. The weakly acidic environment of endosome/lysosome releases M6P receptors and the phosphate ...

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Section: Final Perspectivesmentioning

confidence: 99%

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Dana

Pathak

2020

Molecules

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“…Compared to the analogues, only Cat B stimulated the effective fluorescence recovery of the nanovehicles, exhibiting high selectivity for Cat B among members of the cathepsin family, which could be attributable to the specific recognition and hydrolysis of Pep1. 35 Furthermore, to investigate the dual-enzyme controlled drug release efficiency of the nanovehicles, drug release experiments were carried out in the presence and absence of HAase and Cat B, respectively. Real-time drug release profiles were recorded (Figure 2d).…”

Section: Detection Of Cat B and Dual-enzyme Controlled Drug Release Imentioning

confidence: 99%

Peptide-mediated core/satellite/shell multifunctional nanovehicles for precise imaging of cathepsin B activity and dual-enzyme controlled drug release

Zheng

Zhang

et al. 2017

NPG Asia Mater

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Intracellular imaging of pathologically relevant proteases can provide essential information for the accurate evaluation of disease stage and progression. However, the risks of degradation by nonspecific enzymes during transportation and poor cellular uptake limit the use of peptide-based molecular probes (PMPs) for in situ protease imaging. To overcome these obstacles, a self-protected nanovehicle with a peptide-mediated core/satellite/shell structure was constructed for precise imaging of the protease cathepsin B (Cat B) in situ and the subsequent Cat B-responsive drug release. The self-protected nanovehicles demonstrated excellent resistance to nonspecific enzymolysis, thereby keeping the embedded PMPs intact until they reach the target organelle. Furthermore, the targeting ability of the outer shell facilitated the internalization of nanovehicles into tumor cells via receptor-guided recognition: the protective shell thereafter degraded in the intracellular microenvironment, and Cat B activity was dynamically monitored as the core/satellite structure disassembled. Meanwhile, the peptide-mediated satellite/shell structures served as three-dimensional gatekeepers to lock doxorubicin inside the nanovehicles, and drug release was spatiotemporally controlled by Cat B activity. This study provides important guiding principles for the rational design of self-protected nanovehicles for accurate diagnosis and therapy.

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“…The protease recognition site within the probes is crucial for conferring selectivity. For example, SBPs with high selectivity toward cathepsin B have been used to detect cathepsin B activity in live cancer cells [31] and in dysplastic intestinal adenomas in mice [32]. …”

Section: Protease-targeted Probes For Live-cell Imagingmentioning

confidence: 99%

Pathomimetic cancer avatars for live-cell imaging of protease activity

Heyza

Sloane

2016

Biochimie

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Proteases are essential for normal physiology as well as multiple diseases, e.g., playing a causative role in cancer progression, including in tumor angiogenesis, invasion, and metastasis. Identification of dynamic alterations in protease activity may allow us to detect early stage cancers and to assess the efficacy of anti-cancer therapies. Despite the clinical importance of proteases in cancer progression, their functional roles individually and within the context of complex protease networks have not yet been well defined. These gaps in our understanding might be addressed with: 1) accurate and sensitive tools and methods to directly identify changes in protease activities in live cells, and 2) pathomimetic avatars for cancer that recapitulate in vitro the tumor in the context of its cellular and non-cellular microenvironment. Such avatars should be designed to facilitate mechanistic studies that can be translated to animal models and ultimately the clinic. Here, we will describe basic principles and recent applications of live-cell imaging for identification of active proteases. The avatars optimized by our laboratory are three-dimensional (3D) human breast cancer models in a matrix of reconstituted basement membrane (rBM). They are designated mammary architecture and microenvironment engineering (MAME) models as they have been designed to mimic the structural and functional interactions among cell types in the normal and cancerous human breast. We have demonstrated the usefulness of these pathomimetic avatars for following dynamic and temporal changes in cell:cell interactions and quantifying changes in protease activity associated with these interactions in real-time (4D). We also briefly describe adaptation of the avatars to custom-designed and fabricated tissue architecture and microenvironment engineering (TAME) chambers that enhance our ability to analyze concomitant changes in the malignant phenotype and the associated tumor microenvironment.

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Prodrug-Inspired Probes Selective to Cathepsin B over Other Cysteine Cathepsins

Cited by 43 publications

References 45 publications

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L

Peptide-mediated core/satellite/shell multifunctional nanovehicles for precise imaging of cathepsin B activity and dual-enzyme controlled drug release

Pathomimetic cancer avatars for live-cell imaging of protease activity

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