Calpain inhibitors

Myocardial infarcts Ca2+ homeostasis is lost in ischemic areas, triggering inappropriate calpain activity. Desmin and a-spectrin are degraded in ischemic hearts by synthetic calpain inhibitors. Protein and mRNA levels of m and (./-calpain increase after myocardial infarction40-43... 

Both the 26S proteasome and the RC hydrolyze all four nucleotide triphosphates, with ATP and CTP preferred over GTP and UTP [58]. Although ATP hydrolysis is required for conjugate degradation, the two processes are not strictly coupled. Complete inhibition of the peptidase activity of the 26S proteasome by calpain inhibitor I has little effect on the ATPase activity of the enzyme. The nucleotidase activities of the RC and the 26S proteasome closely resemble those of E. coli Lon protease, which is composed of identical subunits that possess both proteolytic and nucleotidase activities in the same polypeptide chain. Like the regulatory complex and 26S proteasome, Lon hydrolyzes all four ribonucleotide triphosphates, but not ADP or AMP [18]. 

A calpain inhibitor, the DPK of N-dimethyltyrosine, was isolated from Streptomyces griseus and this compound showed activity in the calpain assay as described by Alvarez etal Calpain is a cytosolic protease regulated by calcium and is distributed in mammalian and avian cells. Calpain catalyzes proteolysis of target protein in cells, causing changes in metabolic processes such as the activation of protein kinase C, neuropeptide metabolism, and the activation of platelets. It is proposed that these inhibitors can be used in the treatment of neurodegen-erative diseases. 

Alice et al studied the turnover kinetics of Listeria OTonocytogenex-secreted p60 protein (a murein hydrolase) by host cell cytosolic proteasomes. J774 cells, seeded in flasks and incubated overnight in culture medium, were infected with log-phase cultures of E. monocytogenes for 30 min, washed, and incubated in culture medium for 3 h, with gentamicin (50 tg/ml) added after the first 30 min to inhibit extracellular bacterial growth. Cells then were washed and placed in methionine-free medium with spectinomycin, gentamicin, the eukaryotic protein synthesis inhibitors [cycloheximide (50 tg/mL) and anisomycin (30 tg/ml),] and 25 dVI calpain inhibitor I. After 30 min, [ S]methionine was added, and the cells were pulse-labeled for periods of 20 to 60 min. Cells... 

Sicard RE (2002) Differential inflammatory and immunological responses in tissue regeneration and repair. Ann N Y Acad Sci 961 368-71 Southard JH, Belzer FO (1995) Organ preservation. Annu Rev Med 46 235-247 Stracher A (1999) Calpain inhibitors as therapeutic agents in nerve and muscle degeneration. Ann N Y Acad Sci 884 52-9... 

Ray S. K., Hogan E. L., and Banik N. L. (2003). Calpain in the pathophysiology of spinal cord injury neuroprotection with calpain inhibitors. Brain Res. Rev. 42 169-185. 

Multiple sclerosis. Levels of the 150-kD calpain-specific degradation product of a-spectrin increase 50% in human multiple sclerosis plaques degradation of the 68-kD neurofilament protein is inhibited by a synthetic calpain inhibitor Shields et al., 1999 Banik et al., 1997... 

The occurrence of the proteolytic activity of calpain confirms that abnormal glutamate overactivates the NMDA receptor leading to intracellular calcium overload. Neuroprotection afforded by calpain inhibitors lends further support to the role of glutamate in RGC degeneration (Oka et al., 2006 Sakamoto et al., 2000). 

MI in rats (surgical LAD ligation) Caspase-3 inhibitor II Calpain inhibitor XII Immediately after LAD ligation Reduced size of MI Improved LV function Attenuated LV remodeling Reduced apoptosis [183]... 

Several structures of proteasome inhibitor complexes have been determined by X-ray crystal analysis [22, 50, 51]. Calpain inhibitor I (acetyl-L-L-norleudnal) was covalently bound to Thr-1 of the /91, pi and y95 subunits, respectively. This peptide aldehyde inhibitor is attacked by the threonyl Oy to form a hemiacetal. The nor-leucine side chain projects into a pocket with an opening in its side towards a tunnel leading to the particle surface. The leucine side chain at P2 is not in contact with the protein, whilst the leucine side chain at P3 is in contact with the adjacent / -type subunit. 

Lactacystin is covalently bound to y 5. Its dimethyl side chain at CIO projects into SI like a valine or leucine side chain, but not so deeply as the norleucine side chain of the calpain inhibitor. Lactacystin forms a host of hydrogen bonds with protein main-chain atoms. These hydrogen-bonding interactions could also be present in pi and p2. 

Shi Y, MelnikovVY, Schrier RW, Edelstein CL. Down-regulation of the calpain inhibitor protein, calpastatin, by caspases during renal ischemia. Am J Physiol 2000 279 F509-F517. 

E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. Several E-64 derivatives have been developed [542], Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Call) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegen-erative states, including AD. 

Schiefer IT, Tapadar S, Litosh V, Siklos M, Seism R, Wijewickrama GT et al (2013) Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors. J Med Chem 56 6054-6068... 

Lopez-Picon, F.R., Kukko-Lukjanov, T., and Holopainen, LE., 2006. The calpain inhibitor MDL-28170 and the AMPA/KA receptor antagonist CNQX inhibit neurofilament degradation and enhance neuronal survival in kainic acid-treated hippocampal slice cultures, Eur. J. Neurosci., 23, pp. 2686-2694. 

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