Novel Peptidyl Aryl Vinyl Sulfones as Highly Potent and Selective Inhibitors of Cathepsins L and B

Mendieta, Laura; Picó, Anna; Tarragó, Teresa; Teixidó, Meritxell; Castillo, Marcos; Rafecas, Llorenç; Moyano, Albert; Giralt, Ernest

doi:10.1002/cmdc.201000109

Cited by 29 publications

(26 citation statements)

References 31 publications

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“…Therefore, there were numerous developments. The list of reactive groups used is rather extensive: acyloxymethyl ketones [118], vinyl sulfones [119,120], nitriles [121,122], azepanone-based [123] and allylsulfones [124]. More information can be found in an excellent overview [125].…”

Section: Small-molecule Inhibitors Of Cysteine Cathepsinsmentioning

confidence: 99%

Cysteine cathepsins: From structure, function and regulation to new frontiers

Türk

Stoka

Vasiljeva

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

1,118

1,054

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It is more than 50 years since the lysosome was discovered. Since then its hydrolytic machinery, including proteases and other hydrolases, has been fairly well identified and characterized. Among these are the cysteine cathepsins, members of the family of papain-like cysteine proteases. They have unique reactive-site properties and an uneven tissue-specific expression pattern. In living organisms their activity is a delicate balance of expression, targeting, zymogen activation, inhibition by protein inhibitors and degradation. The specificity of their substrate binding sites, small-molecule inhibitor repertoire and crystal structures are providing new tools for research and development. Their unique reactive-site properties have made it possible to confine the targets simply by the use of appropriate reactive groups. The epoxysuccinyls still dominate the field, but now nitriles seem to be the most appropriate "warhead". The view of cysteine cathepsins as lysosomal proteases is changing as there is now clear evidence of their localization in other cellular compartments. Besides being involved in protein turnover, they build an important part of the endosomal antigen presentation. Together with the growing number of non-endosomal roles of cysteine cathepsins is growing also the knowledge of their involvement in diseases such as cancer and rheumatoid arthritis, among others. Finally, cysteine cathepsins are important regulators and signaling molecules of an unimaginable number of biological processes. The current challenge is to identify their endogenous substrates, in order to gain an insight into the mechanisms of substrate degradation and processing. In this review, some of the remarkable advances that have taken place in the past decade are presented. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

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Section: Small-molecule Inhibitors Of Cysteine Cathepsinsmentioning

confidence: 99%

Cysteine cathepsins: From structure, function and regulation to new frontiers

Türk

Stoka

Vasiljeva

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

1,118

1,054

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“…However, in a separate study by Mendieta et al, the authors developed a structurally novel library of twenty peptidyl 3-aryl vinylsulfones ( Figure 9) in which they introduced extensive diversity at the R1 position. Subsequently, they also varied the R2 position while keeping either morpholine or N-methyl piperazine group intact [116]. Docking studies with most active and selective inhibitor (Entry 15,…”

Section: Peptidyl Aryl Vinylsulfonesmentioning

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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“…Enzyme activity assay and optimum pH Enzyme activity was assayed by cleavage of the fluorescent substrate Z-Arg-Arg-7-amido-4-methylcoumarin hydrochloride (Z-Arg-Arg-AMC, Sigma) according to the method of Mendieta et al (2010). The reaction was conducted in a total volume of 200 μl of assay buffer (100 mM sodium acetate, 5 mM DTT; pH 5.0) coupled with an appropriate quantity of enzyme.…”

Section: Parasitesmentioning

confidence: 99%

Cloning and characterization of a novel cathepsin B-like cysteine proteinase from Angiostrongylus cantonensis

Cheng

Xiao²,

Li³

et al. 2012

Parasitol Res

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Cysteine protease plays a key role in host-parasite interactions. In this study, we identified a novel gene encoding a cathepsin B-like cysteine protease (AcCBL1) from the cDNA library of Angiostrongysus cantonensis fourth-stage larvae (L4) and characterized its biological role in the parasite. Sequence and phylogeny analysis showed that AcCBL1 is related to other cathepsin B family members with the conserved catalytic triad (Cys, His, Asn) and diagnostic occluding loop. In addition, the sequence contains a specific "hemoglobinase motif" and might have a hemoglobinase (Hb)-degrading function. The recombinant AcCBL1 (rAcCBL1) exhibited the protease activity by gelation SDS/PAGE assay; rAcCBL1 can cleave the fluorogenic substrate Z-Arg-Arg-AMC, and the optimum pH was 5.5. The enzyme can hydrolyse several host proteins including Hb and human IgG in acidic pH, but low levels of hydrolysis were observed in neutral pH. Reverse transcription polymerase chain reaction revealed that AcCBL1 expression was detected throughout various developmental stages, L3, L4, adult male and female worms. Western blotting analysis indicated that AcCBL1 was an excretory/secretory product of L4 in mature form of protease. Immunolocalization demonstrated that AcCBL1 was mainly localized in the intestine of L4. These results suggest that rAcCBL1 may play an important role in the parasite nutrition uptake.

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Novel Peptidyl Aryl Vinyl Sulfones as Highly Potent and Selective Inhibitors of Cathepsins L and B

Cited by 29 publications

References 31 publications

Cysteine cathepsins: From structure, function and regulation to new frontiers

Cysteine cathepsins: From structure, function and regulation to new frontiers

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

Cloning and characterization of a novel cathepsin B-like cysteine proteinase from Angiostrongylus cantonensis

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