Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy

Lescop, Cyrille; Herzner, Holger; Siendt, H.; Bolliger, Reto; Henneböhle, M.; Weyermann, Philipp; Briguet, Alexandre; Courdier-Früh, Isabelle; Erb, Michael; Foster, Mark; Meier, Thomas; Magyar, Josef P.; Sprecher, Andreas von

doi:10.1016/j.bmcl.2005.08.064

Cited by 34 publications

(20 citation statements)

References 23 publications

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“…For example, calpains play physiological roles in cell motility (Perrin and Huttenlocher 2002), apoptosis (Squier et al 1994), cell differentiation (Simonson et al 1985), and synaptic transmission (for a review, see Wu and Lynch 2006). On the other hand, calpains are also thought to play roles in the pathogenesis of Huntington's, Parkinson's, and Alzheimer's diseases, cataract formation, diabetes, ischemic and traumatic brain injury, the pathogenesis of stroke, myocardial infarction, and muscular dystrophy (Bevers and Neumar 2008;Higuchi et al 2005;Lescop et al 2005;Ray et al 2003;Saatman et al 1996). Understanding the physiological roles of calpains, on the one hand, and the potential use of calpain inhibitors in preventing pathological processes, on the other, led to the development of a large number of calpain inhibitors (Bevers and Neumar 2008;Ray 2006;Ray et al 2003;Saez et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Calpain Inhibitors Alter the Excitable Membrane Properties of CulturedAplysiaNeurons

Khoutorsky

Spira²

2008

Journal of Neurophysiology

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Khoutorsky A, Spira ME. Calpain inhibitors alter the excitable membrane properties of cultured Aplysia neurons. J Neurophysiol 100: 2784 -2793, 2008. First published August 6, 2008 doi:10.1152/jn.90487.2008. The calpain superfamily of calciumdependent papain-like cysteine proteases constitutes highly conserved proteases that function to posttranslationally modify substrates by partial proteolysis. Calpains are known to proteolyze Ͼ100 substrates that lack strong sequence homology. Consequently, the calpain superfamily has been implicated in playing a central role in diverse physiological and pathological processes. Investigation of the physiological functions of calpains, on the one hand, and the need to develop pharmacological reagents to inhibit calpain-mediated pathological processes, on the other hand, led to the development of numerous calpain inhibitors. Using cultured Aplysia neurons and voltage-clamp analysis, we report here that the calpain inhibitors calpeptin, MG132, and the calpain inhibitor XII inhibit voltage-gated potassium conductance and moderately reduce the sodium conductance. These consequently lead to spike broadening and increased calcium influx. Such alterations of the excitable membrane properties may alter the normal patterns of neuronal and muscle electrical activities and thus should be taken into account when evaluating the effects of calpain inhibitors as protective/therapeutic drugs and as research tools.

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Section: Introductionmentioning

confidence: 99%

Calpain Inhibitors Alter the Excitable Membrane Properties of CulturedAplysiaNeurons

Khoutorsky

Spira²

2008

Journal of Neurophysiology

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“…This intermediate is quite stable and thus low K i values have been observed with peptidyl α- ketoamide transition-state inhibitors. Peptidyl α-ketoamides have been extensively studied by our group36, 38 and other investigators 70–73. Our previous work has shown that extension of the inhibitors to the primed region increased the potency of the inhibitors and N -monosubstituted peptidyl α-ketoamides were more potent than the corresponding N,N -disubstituted peptidyl α-ketoamides 38.…”

Section: Resultsmentioning

confidence: 96%

Peptidyl α-Ketoamides with Nucleobases, Methylpiperazine, and Dimethylaminoalkyl Substituents as Calpain Inhibitors

Ovat

Hampton

et al. 2010

J. Med. Chem.

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A series of peptidyl α-ketoamides with the general structure Cbz-L-Leu-D,L-AA-CONH-R were synthesized and evaluated as inhibitors for the cysteine proteases calpain I, calpain II and cathepsin B. Nucleobases, methylpiperazine and dimethylaminoalkyl groups were incorporated into the primed region of the inhibitors to generate compounds that potentially cross the bloodbrain barrier. Two of these compounds (Cbz-Leu-D,L-Abu-CONH-(CH 2 ) 3 -adenin-9-yl and CbzLeu-D,L-Abu-CONH-(CH 2 ) 3 -(4-methylpiperazin-1-yl) have been shown to have useful concentrations in the brain in animals. The best inhibitor for calpain I was Cbz-Leu-D,L-Abu-CONH-(CH 2 ) 3 -2-methoxyadenin-9-yl (K i = 23 nM) and the best inhibitor for calpain II was CbzLeu-D,L-Phe-CONH-(CH 2 ) 3 -adenin-9-yl (K i = 68 nM). Based on the crystal structure obtained with heterocyclic peptidyl α-ketoamides, we have improved inhibitor potency by introducing a small hydrophobic group on the adenine ring. These inhibitors have good potential to be used in the treatment of neurodegenerative diseases.

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“…Racemization of the compounds is consistent with previous reports, which indicate that α–keto carbonyl compounds are prone to racemization in the presence of base. 11…”

Section: Resultsmentioning

confidence: 99%

Structural Basis for the Potent Calpain Inhibitory Activity of Peptidyl α-Ketoacids

2008

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Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy

Cited by 34 publications

References 23 publications

Calpain Inhibitors Alter the Excitable Membrane Properties of CulturedAplysiaNeurons

Calpain Inhibitors Alter the Excitable Membrane Properties of CulturedAplysiaNeurons

Peptidyl α-Ketoamides with Nucleobases, Methylpiperazine, and Dimethylaminoalkyl Substituents as Calpain Inhibitors

Structural Basis for the Potent Calpain Inhibitory Activity of Peptidyl α-Ketoacids

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