E-64-c
E-64-c, which is also known as Ep-475, is an analog of E-64 and inhibitor of cysteine proteinases. [1]
The cysteine proteinases, of which Cathepsins B and H and cathepsin L exist in mammals, contain an essential highly reactive thiol group, and therefore are inhibited by thiol-blocking reagents such as iodoacetate and mercuribenzoate. E-64-c showed promise of acting as class-specific inhibitors for the cysteine proteinases. X-ray diffraction shows that E-64-c binds to papain through a thioether covalent bond.[1]
E-64-c, which is an analog of E-64, has proved to be substantially more reactive than E-64 with cathepsins B and L. Cathepsins B and H from human liver and rat cathepsin L were used to measure the rate constants of inhibition of E-64-c, which indicated the rate constants of inactivation of cathepsins B, H and L were 298000, 2018, 206000 M-1 s-1 , respectively[2].
E-64-c was injected subcutaneously, in various doses, daily for 80 days into dystrophic chickens, the activities of cathepsin B and cathepsin H were reduced to the levels in control chickens. E-64-c showed dose-dependent activities on inhibiting cathepsin H and B. However, cathepsin D is not sensitive to E-64-c. Moreover, 10 mg/kg per 8 h of an oil emulsion of E-64-c injection reduced protein degradation 20% in muscles from burned rats. E-64c, which also inhibits calpain , was administered at a dose of 400 mg/kg twice a day for 3 days to middle cerebral artery occlusion mice. The MAP2 levels was increased compared to control and the depletion was significantly inhibited.[3,4]
References:
1.Yamamoto D, Matsumoto K, Ohishi H, et al. Refined x-ray structure of papain. E-64-c complex at 2.1-A resolution[J]. Journal of Biological Chemistry, 1991, 266(22): 14771-14777.
2.Barrett A J, Kembhavi A A, Brown M A, et al. L-trans-Epoxysuccinyl-leucylamido (4-guanidino) butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L[J]. Biochem. J, 1982, 201: 189-198.
3.Clark A S, Kelly R A, Mitch W E. Systemic response to thermal injury in rats. Accelerated protein degradation and altered glucose utilization in muscle[J]. Journal of Clinical Investigation, 1984, 74(3): 888.
4.Inuzuka T, Tamura A, Sato S, et al. Suppressive effect of E-64c on ischemic degradation of cerebral proteins following occlusion of the middle cerebral artery in rats[J]. Brain research, 1990, 526(1): 177-179.
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 314.4 |
| Cas No. | 76684-89-4 |
| Formula | C15H26N2O5 |
| Solubility | ≥31.4 mg/mL in DMSO; insoluble in H2O; ≥111.8 mg/mL in EtOH |
| Chemical Name | (2S,3S)-3-[[(2S)-4-methyl-1-(3-methylbutylamino)-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylic acid |
| SDF | Download SDF |
| Canonical SMILES | CC(C)CCNC(=O)C(CC(C)C)NC(=O)C1C(O1)C(=O)O |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
Neuronal chromaffin cells |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
10 μM |
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Applications |
In neuronal chromaffin cells, E-64-c inhibited the production of the 12 ~ 14 kDa β-secretase product from APP. In addition, when tested in isolated, intact secretory vesicles, E-64-c reduced the production of Aβ (1 ~ 40). These results indicated an important role of E-64-c in β-secretase processing of APP in neuronal chromaffin cells. |
| Animal experiment [2]: | |
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Animal models |
Rat models of cerebral ischemia |
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Dosage form |
400 mg/kg; i.p.; b.i.d, for 3 days |
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Applications |
In rat models of cerebral ischemia, E-64-c significantly inhibited the ischemia-induced depletion of microtubule-associated protein 2 (MAP2). E-64-c increased MAP2 levels to 55 ± 25.7% of control levels (sham-operated rats used as controls). However, E-64-c showed no marked effect on the decrease of myelin-associated glycoprotein caused by ischemia. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Hook VY, Reisine TD. Cysteine proteases are the major beta-secretase in the regulated secretory pathway that provides most of the beta-amyloid in Alzheimer's disease: role of BACE 1 in the constitutive secretory pathway. J Neurosci Res. 2003 Nov 1;74(3):393-405. [2]. Inuzuka T, Tamura A, Sato S, et al. Suppressive effect of E-64c on ischemic degradation of cerebral proteins following occlusion of the middle cerebral artery in rats[J]. Brain research, 1990, 526(1): 177-179. | |
| E-64-c is an effective synthetic calpain inhibitor composed from E-64, which also inhibits cathepsin B, cathepsin H, and cathepsin L (cysteine proteases). | ||||||
| Targets | cathepsins B | cathepsins H | cathepsins L | |||
| IC50 | ||||||
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Chemical structure
