Cathepsin S inhibitors: 2004 – 2010

Lee-Dutra, Alice; Wiener, Danielle K.; Sun, Siquan

doi:10.1517/13543776.2011.553800

Cited by 54 publications

(57 citation statements)

References 54 publications

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“…These compounds have been designed to engage the active site of the target protease and bind to catalytic cysteine residue via the employment of a warhead that is typically electrophilic in nature (Chang et al, 2007). The types of warheads that have been utilised are either irreversible (epoxide, Michael acceptor, α-haloketone) or reversible (cyano, ketoamide) in design (Lee-Dutra et al, 2011).…”

Section: The Therapeutic Utility Of Cathepsin Smentioning

confidence: 99%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

174

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: The Therapeutic Utility Of Cathepsin Smentioning

confidence: 99%

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Wilkinson

Williams

Scott

et al. 2015

Biological Chemistry

174

139

View full text Add to dashboard Cite

show abstract

“…In-depth analysis of the crystal structure of the CatS highlighted that the S2 and S3 subsites were important to achieve selectivity towards CatS [119,120]. Selective targeting is known to be an issue with many cathepsin inhibitors, and much effort has been dedicated to the development of selectivity whilst maintaining potency [121][122][123]. However, the inherent problems in achieving specific targeting of CatS is not only due to high homology within the active site of several other related family members such as CatL and CatK, but also due to the resultant lysosomotrophism, where accumulation of inhibitors in cathepsin rich organs can result in decreased specificity and increased toxicity issues [124].…”

Section: Cathepsin S Inhibitorsmentioning

confidence: 99%

The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Small

Burden

Scott

2011

Clinic Rev Bone Miner Metab

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Cathepsin S is a lysosomal cysteine protease that has been shown to play a key role in MHC class II antigen presentation. Consequently, it has been extensively evaluated as a therapeutic target in autoimmune diseases, such as rheumatoid arthritis and psoriasis. Additionally, clinical and mechanistic evidence is emerging, revealing its inappropriate expression and secretion in a wide range of disease states including atherosclerosis and tumourigenesis. This review covers the known role and consequences of cathepsin S activity in these pathological disorders, highlighting various studies that have demonstrated its utility as a therapeutic target. This review also examines challenges that exist towards the development of agents that specifically target this protease and discusses the studies to date that have applied cathepsin S inhibitors in disease models.

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“…During this process, cysteine cathepsins are believed to be intimately involved in the processing of both the myelin-associated antigens and Ii of MHC-II. Several studies have shown that cathepsin S inhibitors can attenuate EAE and other autoimmune models, suggesting that cathepsin S may be a specific therapeutic target for MS [10, 16, 25–27]. In particular, the compound LHVS has been suggested to selectively inhibit cathepsin S and attenuate EAE [12, 16].…”

Section: Introductionmentioning

confidence: 99%

“…Despite years of interest in therapeutically targeting cysteine cathepsins in MS, and sporadic autoimmune clinical trials of lead compounds that inhibit cathepsin S [27], EAE has not been attempted in mice genetically deficient in individual cysteine cathepsins. Hence, the importance of cathepsins B, S, and L as specific therapeutic targets for MS remain unsubstantiated in an animal model.…”

Section: Introductionmentioning

confidence: 99%

Redundancy between Cysteine Cathepsins in Murine Experimental Autoimmune Encephalomyelitis

Allan

Yates

2015

PLoS ONE

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The cysteine cathepsins B, S, and L are functionally linked to antigen processing, and hence to autoimmune disorders such as multiple sclerosis. Stemming from several studies that demonstrate that mice can be protected from experimental autoimmune encephalomyelitis (EAE) through the pharmacologic inhibition of cysteine cathepsins, it has been suggested that targeting these enzymes in multiple sclerosis may be of therapeutic benefit. Utilizing mice deficient in cysteine cathepsins both individually and in combination, we found that the myelin-associated antigen myelin oligodendrocyte glycoprotein (MOG) was efficiently processed and presented by macrophages to CD4+ T cells in the individual absence of cathepsin B, S or L. Similarly, mice deficient in cathepsin B or S were susceptible to MOG-induced EAE and displayed clinical progression and immune infiltration into the CNS, similar to their wild-type counterparts. Owing to a previously described CD4+ T cell deficiency in mice deficient in cathepsin L, such mice were protected from EAE. When multiple cysteine cathepsins were simultaneously inhibited via genetic deletion of both cathepsins B and S, or by a cathepsin inhibitor (LHVS), MHC-II surface expression, MOG antigen presentation and EAE were attenuated or prevented. This study demonstrates the functional redundancy between cathepsin B, S and L in EAE, and suggests that the inhibition of multiple cysteine cathepsins may be needed to modulate autoimmune disorders such as multiple sclerosis.

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Cathepsin S inhibitors: 2004 – 2010

Cited by 54 publications

References 54 publications

Cathepsin S: therapeutic, diagnostic, and prognostic potential

Cathepsin S: therapeutic, diagnostic, and prognostic potential

The Emerging Relevance of the Cysteine Protease Cathepsin S in Disease

Redundancy between Cysteine Cathepsins in Murine Experimental Autoimmune Encephalomyelitis

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