ABSTRACT
The ongoing coronavirus disease 2019 (COVID-19) pandemic has raised an urgent need to develop effective therapeutics against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As a potential antiviral drug target, the nucleocapsid (N) protein of SARS-CoV-2 functions as a viral RNA chaperone and plays vital and multifunctional roles during the life cycle of coronavirus1-3. In this study, we discovered that the N protein of SARS-CoV-2 undergoes liquid-liquid phase separation (LLPS) both in vitro and in vivo, which is further modulated by viral RNA. In addition, we found that, the core component of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, nsp12, preferentially partitions into the N protein condensates. Moreover, we revealed that, two small molecules, i.e., CVL218 and PJ34, can be used to intervene the N protein driven phase separation and loosen the compact structures of the condensates of the N-RNA-nsp12 complex of SARS-CoV-2. The discovery of the LLPS-mediated interplay between N protein and nsp12 and the corresponding modulating compounds illuminates a feasible way to improve the accessibility of antiviral drugs (e.g., remdesivir) to their targets (e.g., nsp12/RdRp), and thus may provide useful hints for further development of effective therapeutic strategies against SARS-CoV-2.
ABSTRACT
The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.
ABSTRACT
AIM: To investigate the effect of l menthol on percutaneous absorption of metronidazole through changing the skin character in rabbits. METHODS: Using rabbit skin with different character as transdermal barrier, and l menthol as transdermal enhancer, the absorbance of metronidazole was determined with a two cells diffusion apparatus in vitro, and its permeability was figured out. RESULTS: The transdermal action of l menthol on percutaneous absorption of metronidazole was very evident when the corneum was eliminated; l menthol and azone could increase the desposit function of metronidazole in the intact skin, but had no effect on the skin without corneum. The result also showed that the percutaneous absorption and intact skins desposit function of metronidazole had no difference between l menthol and azone. CONCLUSION: L menthol can increase the percutaneous absorption of metronidazole. The site of the action is mainly the corneum which has desposit function.
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AIM: To compare the permeation enhancing characters of menthol and azone on the model drug of indomethacin and to study the enhancing effect when the two agents were used in combination. METHODS: The transdermal test was conduced on the penetration experiment apparatus of isolated skin. The cumulate penetrated amount, penetrating rate, stable flux and lag time were calculated upon the concentrations. RESULTS: After adding the penetration enhancer, the penetrating rate of indomethacin increased remarkably. It was 6.21 , 4.91 and 6.92 times of that of the controls respectively. When used in combination, the two penetration enhancers increased much more the penetrating rate than being used separately (P
ABSTRACT
AIM: To study the enhancing effect of penetration enhancer on percutaneous absorption of antifungal agents. METHODS: Percutaneous penetration experiment was performed on device in vitro, and the deposit effects were observed with vivoperception. RESULTS: Combination of 1-menthol (1%) and azone (1%) showed the best effect on percutaneous absorption of cidopicox olamine, and 1-menthol (1%) had the best effect on percutaneous absorption of salysic acid. The compound penetration enhancer, consisting of 1-menthol (1%), azone (1%), propylene glycol ( 2.5%) and oleic acid ( 2.5%), had prominent action on absorption of cidopirox olamine through rabbit skins, and shorten the lag times obviously. CONCLUSION: L-menthol and azone can significantly enhance the percutaneous absorption of both salysic acid and cidopicox olamine. Combination of 1-menthol and azone can further increase the absorption.c
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OBJECTIVE:To observe the antifungal activity of azone against dermatophytes and candida albicans.METHO_ DS:The MIC of azone was determined by NCCLS M27,M38method and MTT assay.MFC was also determined.RESULTS:MIC and MFC of azone against dermatophytes were0.02%and0.08%respectively.CONCLUSION:Azone has significant action in inhibiting candida albicans and fungicidal effect on dermatophytes.
ABSTRACT
OBJECTIVE:Indomethacinum(Ind) and diclofenac sodium(Dcs) were taken as model drugs to study the enhancing effect of l-menthol on percutaneous absorption of two compounds with different characteristics,and to probe into the effect of combined use of l-menthol with azone.METHODS:Percutaneous penetration experiment was performed on in vitro device and deposit effect was observed with vivoperception.RESULTS:l-menthol could significantly enhance the percutaneous absorption and shorten the lag times(T1ag) of both Ind and Dcs.The enhancing effects of l-menthol,used either alone or in combination with azone,were several times stronger on Ind than on Dcs.Combined use of two enhances was more effective in enhancing penetration and longer in T1ag than single use of l-menthol,especially for Dcs.The study on deposit effect showed that l-menthol could increase the penetration rate than control agent(P