Evaluation of a novel calpain inhibitor as a treatment for cataract

Lee, Hannah Y.‐Y.; Morton, James D.; Robertson, Lucinda J. G.; McDermott, J. D.; Bickerstaffe, R.; Abell, Andrew D.; Jones, Matthew A.; Mehrtens, Janna M.; Coxon, James M.

doi:10.1111/j.1442-9071.2009.01925.x

Cited by 14 publications

(16 citation statements)

References 40 publications

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“…Calpain inhibitors have been widely used to investigate the role of this protease under physiological and pathological conditions (Ai et al, 2007;Azuma and Shearer, 2008;Carragher, 2006;Frederick et al, 2008;Hoang et al, 2011;Lee et al, 2008a;Logie et al, 2005;Neuhof et al, 2004;Samantaray et al, 2008). Numerous calpain inhibitors have been synthesized [reviewed in (DePetrillo, 2002;Pietsch et al, 2010)].…”

Section: Peptide and Non-peptide Inhibitors Of Calpainmentioning

confidence: 99%

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

Curcio

Salazar

Mele

et al. 2016

Progress in Neurobiology

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Section: Peptide and Non-peptide Inhibitors Of Calpainmentioning

confidence: 99%

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

Curcio

Salazar

Mele

et al. 2016

Progress in Neurobiology

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“…The application of SJA-6017 (or a related peptide aldehyde (8a), Fig. (8), see below) to the eyes of sheep with hereditary cataract significantly retarded the development of cataract in the treated eye compared to untreated eye [233,234].…”

Section: Peptide Aldehydesmentioning

confidence: 98%

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Pietsch

Chua²,

Abell

2010

CTMC

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The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.

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“…There is abundant evidence that calpain-mediated proteolysis is important during cataract progression [108 -113], and novel calpain inhibitors are being developed as potential new treatments for cataract [114,115]. There is also now emerging evidence of a role for calpains in lens fibre cell differentiation and/or organelle loss.…”

Section: Proteolysis Dna Degradation and Dna Repair (A) Caspases Andmentioning

confidence: 99%

Lens fibre cell differentiation and organelle loss: many paths lead to clarity

Wride

2011

Phil. Trans. R. Soc. B

179

152

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The programmed removal of organelles from differentiating lens fibre cells contributes towards lens transparency through formation of an organelle-free zone (OFZ). Disruptions in OFZ formation are accompanied by the persistence of organelles in lens fibre cells and can contribute towards cataract. A great deal of work has gone into elucidating the nature of the mechanisms and signalling pathways involved. It is apparent that multiple, parallel and redundant pathways are involved in this process and that these pathways form interacting networks. Furthermore, it is possible that the pathways can functionally compensate for each other, for example in mouse knockout studies. This makes sense given the importance of lens clarity in an evolutionary context. Apoptosis signalling and proteolytic pathways have been implicated in both lens fibre cell differentiation and organelle loss, including the Bcl-2 and inhibitor of apoptosis families, tumour necrosis factors, p53 and its regulators (such as Mdm2) and proteolytic enzymes, including caspases, cathepsins, calpains and the ubiquitinproteasome pathway. Ongoing approaches being used to dissect the molecular pathways involved, such as transgenics, lens-specific gene deletion and zebrafish mutants, are discussed here. Finally, some of the remaining unresolved issues and potential areas for future studies are highlighted.

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Evaluation of a novel calpain inhibitor as a treatment for cataract

Abstract: In vitro assays confirmed CAT0059 to be a potent calpain inhibitor. The two in vivo trials addressed the ability of CAT0059 to reach the lens and established its limitations as a therapeutic molecule for cataract treatment.

Cited by 14 publications

References 40 publications

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

Lens fibre cell differentiation and organelle loss: many paths lead to clarity

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