Antiviral effects and tissue exposure of tetrandrine against SARS-CoV-2 infection and COVID-19.

Tetrandrine (TET) has been used to treat silicosis in China for decades. The aim of this study was to facilitate rational repurposing of TET against SARS-CoV-2 infection. In this study, we confirmed that TET exhibited antiviral potency against SARS-CoV-2 in the African green monkey kidney (Vero E6), human hepatocarcinoma (Huh7), and human lung adenocarcinoma epithelial (Calu-3) cell lines. TET functioned during the early-entry stage of SARS-CoV-2 and impeded intracellular trafficking of the virus from early endosomes to endolysosomes. An in vivo study that used adenovirus (AdV) 5-human angiotensin-converting enzyme 2 (hACE2)-transduced mice showed that although TET did not reduce pulmonary viral load, it significantly alleviated pathological damage in SARS-CoV-2-infected murine lungs. The systemic preclinical pharmacokinetics were investigated based on in vivo and in vitro models, and the route-dependent biodistribution of TET was explored. TET had a large volume of distribution, which contributed to its high tissue accumulation. Inhaled administration helped TET target the lung and reduced its exposure to other tissues, which mitigated its off-target toxicity. Based on the available human pharmacokinetic data, it appeared feasible to achieve an unbound TET 90% maximal effective concentration (EC90) in human lungs. This study provides insights into the route-dependent pulmonary biodistribution of TET associated with its efficacy.

Effects of konjac glucomannan on the long-term retrogradation and shelf life of boiled wheat noodles.

BACKGROUND: Starch retrogradation and moisture migration of boiled wheat noodles (BWNs) result in quality deterioration and short shelf life. The objective of this research was to investigate whether konjac glucomannan (KGM) could improve the quality of BWNs and further establish the shelf-life prediction model. RESULTS: The moisture distribution, recrystallization, and thermal properties of BWNs during refrigerated or ambient temperature storage were determined. Low-field nuclear magnetic resonance data showed that KGM addition induced left-shifts of T21 and T22 values, indicating that KGM limited the mobility of bound and immobile water among noodle matrices. X-ray diffraction spectra revealed that KGM did not change the crystal patterns of BWNs but could inhibit the starch recrystallization after refrigerated storage. The Tp and ΔH values of retrograded samples notably (P < 0.05) decreased with the increase of KGM addition, suggesting the hinderance of starch retrogradation behavior by KGM. The shelf life of BWNs was predicted by accelerated storage test combined with the Arrhenius equation. The present data displayed that the predicted shelf life of vacuum-packed and sterilized BWNs with 10 g kg-1 KGM at 25 °C was 733 days, 2.4-fold that of the control group. CONCLUSION: BWNs with KGM addition could inhibit starch retrogradation and improve the storage stability, consequently promoting noodle quality. © 2021 Society of Chemical Industry.

Time-Varying Spatial Memory Model and Its Impact on Virus Spreading

The models of time-varying network have a profound impact on the study of virus spreading on the networks. On the basis of an activity-driven memory evolution model, a time-varying spatial memory model (TSM) is proposed. In the TSM model, the cumulative number of connections between nodes is recorded, and the spatiality of nodes is considered at the same time. Therefore, the active nodes tend to connect the nodes with high intimacy and close proximity. Then, the TSM model is applied to epidemic spreading, and the epidemic spreading on different models is compared. To verify the universality of the TSM model, this model is also applied to rumor spreading, and it is proved that it can also play a good inhibiting effect. We find that, in the TSM network, the introduction of spatiality and memory can slow down the propagation speed and narrow the propagation scope of disease or rumor, and memory is more important. We then explore the impact of different prevention and control methods on pandemic spreading to provide reference for COVID-19 management control and find when the activity of node is restricted, the spreading will be controlled. As floating population has been acknowledged as a key parameter that affects the situation of COVID-19 after work resumption, the factor of population mobility is introduced to calculate the interregional population interaction rate, and the time-varying interregional epidemic model is established. Finally, our results of infectious disease parameters based on daily cases are in good agreement with the real data, and the effectiveness of different control measures is evaluated.

Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro.

The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virus-encoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen [marketed as Kaletra®, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration. Nevertheless, the structure-activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.

Anti-SARS-CoV-2 Potential of Artemisinins In Vitro.

The discovery of novel drug candidates with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potential is critical for the control of the global COVID-19 pandemic. Artemisinin, an old antimalarial drug derived from Chinese herbs, has saved millions of lives. Artemisinins are a cluster of artemisinin-related drugs developed for the treatment of malaria and have been reported to have multiple pharmacological activities, including anticancer, antiviral, and immune modulation. Considering the reported broad-spectrum antiviral potential of artemisinins, researchers are interested in whether they could be used to combat COVID-19. We systematically evaluated the anti-SARS-CoV-2 activities of nine artemisinin-related compounds in vitro and carried out a time-of-drug-addition assay to explore their antiviral mode of action. Finally, a pharmacokinetic prediction model was established to predict the therapeutic potential of selected compounds against COVID-19. Arteannuin B showed the highest anti-SARS-CoV-2 potential with an EC50 of 10.28 ± 1.12 µM. Artesunate and dihydroartemisinin showed similar EC50 values of 12.98 ± 5.30 µM and 13.31 ± 1.24 µM, respectively, which could be clinically achieved in plasma after intravenous administration. Interestingly, although an EC50 of 23.17 ± 3.22 µM was not prominent among the tested compounds, lumefantrine showed therapeutic promise due to high plasma and lung drug concentrations after multiple dosing. Further mode of action analysis revealed that arteannuin B and lumefantrine acted at the post-entry step of SARS-CoV-2 infection. This research highlights the anti-SARS-CoV-2 potential of artemisinins and provides leading candidates for anti-SARS-CoV-2 drug research and development.