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SARS-CoV-2 main protease (Mpro) is one of the most extensively exploited drug targets for COVID-19. Structurally disparate compounds have been reported as Mpro inhibitors, raising the question of their target specificity. To elucidate the target specificity and the cellular target engagement of the claimed Mpro inhibitors, we systematically characterize their mechanism of action using the cell-free FRET assay, the thermal shift-binding assay, the cell lysate Protease-Glo luciferase assay, and the cell-based FlipGFP assay. Collectively, our results have shown that majority of the Mpro inhibitors identified from drug repurposing including ebselen, carmofur, disulfiram, and shikonin are promiscuous cysteine inhibitors that are not specific to Mpro, while chloroquine, oxytetracycline, montelukast, candesartan, and dipyridamole do not inhibit Mpro in any of the assays tested. Overall, our study highlights the need of stringent hit validation at the early stage of drug discovery.
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Ebselen (EbSe) is a synthetic lipo-soluble selenium-containing organic small molecule compound with a wide range of physiological and pharmacological activities. EbSe is one of the most well-studied selenium-containing compounds. Early studies have shown that EbSe possess various bio-activities by eliminating intracellular oxygen free radicals and inhibiting lipid peroxidation. Recent studies have demonstrated that the multifarious biological activities of EbSe based on its selenium effect on the cysteine residues of substrates. Its potential clinical application range keeps expanding, which has a prospect application in the treatment of multiple system diseases in the human body. In addition, the latest study confirmed that EbSe has outstanding antibacterial activity against multidrug-resistant bacteria infections. Based on this, this article briefly reviews the research progress of pharmacological activities and related clinical applications of EbSe, providing some references for scientific research and clinical workers.
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BACKGROUND AND OBJECTIVES: The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-β-cyclodextrin (HPβCD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HPβCD could partially resolve the symptoms in both animals and human patients. Despite its desirable effect, HPβCD can induce hearing loss, which is the only major side effect noted to date. Understanding of the pathophysiology of hearing impairment after administration of HPβCD and further development of preventive methods are essential to reduce the ototoxic side effect. The mechanisms of HPβCD-induced ototoxicity remain unknown, but the resulting pathology bears some resemblance to other ototoxic agents, which involves oxidative stress pathways. To indirectly determine the involvement of oxidative stress in HPβCD-induced ototoxicity, we tested the efficacy of an antioxidant reagent, ebselen, on the extent of inner ear side effects caused by HPβCD. MATERIALS AND METHODS: Ebselen was applied prior to administration of HPβCD in mice. Auditory brainstem response thresholds and otopathology were assessed one week later. Bilateral effects of the drug treatments also were examined. RESULTS: HPβCD-alone resulted in bilateral, severe, and selective loss of outer hair cells from base to apex with an abrupt transition between lesions and intact areas. Ebselen co-treatment did not ameliorate HPβCD-induced hearing loss or alter the resulting histopathology. CONCLUSIONS: The results indirectly suggest that cochlear damage by HPβCD is unrelated to reactive oxygen species formation. However, further research into the mechanism(s) of HPβCD otopathology is necessary.
Subject(s)
Animals , Humans , Mice , Ear, Inner , Evoked Potentials, Auditory, Brain Stem , Hair Cells, Auditory, Outer , Hearing Loss , Hearing , Oxidative Stress , Pathology , Reactive Oxygen Species , Sphingolipidoses , Tight JunctionsABSTRACT
Organoselenium compounds are bioactive substances with extensive physiological activities .As a representa-tive compound ,ebselen could be used as mimics of glutathione peroxidase ,and in the treatment of many diseases ,such as car-diovascular and cerebrovascular diseases ,inflammation and noise-induced hearing loss .the research progress in physiological activities and synthetic methods of ebselen were reviewed in this paper .
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Objective To investigate the protective effect of Ebselen on mitochondrial damage and its influence to Cytochrome C expression and the neuronal apoptosis after spinal cord injury in rats. Methods Sixty adult SD rats were ran-domly divided into 5 groups (12 each group). Spinal cord injury model was made using Allen's method. Sham operation group received only laminectomy;SCI group received laminectomy and spinal trauma;Saline group received saline injection intraperitoneally (0.1%DMSO) after injury;methylprednisolone group received 30 mg/kg methylprednisolone injection intra-peritoneally, ebselen group received 10 mg/kg ebselen injection intraperitoneally. The malonaldehyde (MDA) and glutathi-one (GSH)level at the injured sites of the spinal cord were detected 24 hours after trauma, and the expression level of Cyto-chrome C was also observed. Finally, neuronal apoptosis was identified by TUNEL staining. Results MDA level in the Eb-selen group was significantly lower than that in the SCI group, and GSH level was significantly elevated in the Ebselen group compared with SCI group (P<0.01). Expression of Cytochrome C in Ebselen group was lower than that in SCI group shown by Western blot, and the neuronal apoptosis in Ebselen group reduced significantly too compared with SCI group (P<0.01). Conclusion Ebselen can alleviate peroxidation,prohibit expression of Cytochrome C and inhibit neuronal apoptosis,thus it shows a protective effect to experimental acute SCI.
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Objective To evaluate the effect of Ebselen on the ischemia-reperfusion injury (IRI) in rat lungs from non-heart-beating donors (NHBD).Methods Forty Sprague-Dawley rats were paired randomly divided into two groups:group Ⅰ,NHBD with 30 min of warm ischemia time (WIT); group Ⅱ,NHBD with 30 min of WIT and administration of Ebselen.The donor lungs remained ventilated at the room temperature for 30 min after asystolia and then flushed with LPD solution.The recipient rats underwent left lung transplantation.The recipients of group Ⅱ were administered with Ebselen (500 mg/kg body weight) one h before transplantation.Results All the recipients survived during the observation period.In the group Ⅱ,the MDA of the pulmonary tissue was 0.631 ± 0.23 nrmol/mg protein,and the polymorphonuclear neutrophils and the total protein of the bronchoalveolar lavage fluid were (78.4 ± 35.2) × 107/L and (0.41 ± 0.12) mg/ml respectively.The MPO was (25.09 ± 1.19) ％ and W/D was 0.359 ± 0.017.There was significant difference between group Ⅱ and group Ⅰ (all P＜ 0.05).Conclusion The administration of ebselen is an effective treatment to attenuate the acute injury resulted from the ischermia-reperfusion in the rat lungs from non-heart-beating donors.
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Objective:To investigate the electronic structures,spectral properties of ebselen and its carboxylic derivatives and their relationship.Methods:Ebselen and its carboxylic derivatives were optimized by using density functional theory at the B3LYP/6-31+G level,the characteristics of the frontier molecular orbital and the distribution of energy levels were analyzed.Time depended density function theory methods were employed to calculated electronic structure and spectral properties of ebselen and its carboxylic derivatives. Results:There is an angle between benzisoselenazol ring and benzene ring;the absorption spectra mainly originates from the?→? electronic transition.Conclusion:The carboxyl in o-position of benzene ring may increase the dihedral angle between benzisoselenazol ring and benzene ring,and causes a red shift of UV spectra.
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BACKGROUND AND OBJECTIVES: With the advancement of modern civilization and mechanical development of society, the prevalence of noiseinduced hearing loss is increasing. There were some suggestions that noise-induced hearing loss may be reduced or prevented with antioxidant treatment. The purpose of this study is to evaluate the effect of ebselen as a free radical scavenger or antioxidant in noise-induced cochlear damage. MATERIALS AND METHOD: Thirty male Sprague Dawley rats (250-300 g) with normal auditory brainstem response (ABR) thresholds were exposed for 6 h to 115 dB SPL broad band noise. 10 mg/kg ebselen were injected intraperitoneally at 12 h before and 1h before noise exposure. After noise exposure, auditory brainstem response threshold shifts were evaluated. A study for iNOS and nitrotyrosine expressions in the cochlea was examined by immunohistochemical staining. RESULTS: After the noise exposure, auditory brainstem responses indicated that ebselen treatment reduced threshold shifts significantly. The expression of iNOS and nitrotyrosine were observed in hair cells, supporting cells of the organ of Corti, stria vascularis and spiral ganglion. The expression of iNOS and nitrotyrosine were lower in the ebselen treated group than in the non-treated group. CONCLUSION: Ebselen protects cochlea from noise by playing a role as a scavenger of reactive free radicals.
Subject(s)
Humans , Male , Civilization , Cochlea , Evoked Potentials, Auditory, Brain Stem , Free Radicals , Hair , Hearing Loss , Hearing Loss, Noise-Induced , Noise , Organ of Corti , Prevalence , Rats, Sprague-Dawley , Spiral Ganglion , Stria VascularisABSTRACT
BACKGROUND AND OBJECTIVES: Although the mechanism of ozone-induced airway inflammation and hyperresponsiveness is largely unknown, NO and peroxynitrite has been suggested to be associated with it. Ebselen, a seleno-organic compound, is known to inhibit the production of superoxide, iNOS-related NO, and their combined product, peroxynitrite. The purpose of this study is to investigate whether ebselen suppress ozone-induced nasal inflammation and whether ebselen inhibit the production of NO and peroxynitrite in nasal mucosa. SUBJECTS AND METHOD: Thirty-six BALB/c mice were divided into three groups: control group, ozone exposure group, and ozone+ebselen treated group. In the ozone exposure group, mice were exposed to 1 ppm ozone for 8 hours a day for 3 consecutive days. In the ebselen treated group, the ebselen (32.5 mg/kg) solution was injected intraperitoneally 1 hour before and 3 hours after the ozone exposure. At 18 hours of the last ozone exposure, Evans blue was infused via tail vein in 6 animals of each group. Mice were sacrificed five minutes later and nasal mucosa was obtained to measure the amount of extravasated Evans blue dye. From the remaining 6 animals in each group, nasal lavage fluid (NLF) was obtained to measure the concentration of albumin and the number of neutrophils. After lavage fluid was obtained, nasal mucosa was taken for immunohistochemical staining against iNOS and nitrotyrosine usng the ABC method. RESULTS: Extravasation of Evans blue was significantly increased in the ozone exposure group, but it was significantly decreased in the ebselen treated group. Albumin concentration in NLF showed a tendency to increase in the ozone exposure group and a tendency to decrease in the ebselen treated group when compared with the ozone exposure group. The number of neutrophils was significantly increased in the ozone exposure group and was decreased more in the ebselen treated group than in the ozone exposure group. Immunoreactivity to iNOS and nitrotyrosine was strongly expressed in nasal mucosa of the ozone exposure group. However, it was nearly abolished by the treatment with ebselen. CONCLUSIONS: These results may suggest that ebselen can be applied as a useful therapeutic agent for airway diseases by modulating the oxidant-related inflammatory process.