Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines.

AIMS: Angiotensin-converting enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2. MAIN METHODS: Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB inhibitor treatment. Surface ACE2 expression and intracellular reactive oxygen species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay. KEY FINDINGS: Pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells. SIGNIFICANCE: These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations.

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.

Epidemiological changes on the Isle of Wight after the launch of the NHS Test and Trace programme: a preliminary analysis.

Background: In May 2020, the UK National Health Service (NHS) Test and Trace programme was launched in England in response to the COVID-19 pandemic. The programme was first rolled out on the Isle of Wight and included version 1 of the NHS contact tracing app. The aim of the study was to make a preliminary assessment of the epidemiological impact of the Test and Trace programme using publicly available data. Methods: We used COVID-19 daily case data from Public Health England to infer incidence of new infections and estimate the reproduction number (R) for each of the 150 Upper-Tier Local Authorities (UTLAs) in England and nationally, before and after the launch of the Test and Trace programme on the Isle of Wight. We used Bayesian and maximum-likelihood methods to estimate R and compared the Isle of Wight with other UTLAs using a synthetic control method. Findings: We observed significant decreases in incidence and R on the Isle of Wight immediately after the launch of the Test and Trace programme. The Isle of Wight had a marked reduction in R, from 1·3 before the Test and Trace programme to 0·5 after by one of our measures, and went from having the third highest R before the Test and Trace programme, to the twelfth lowest afterwards compared with other UTLAs. Interpretation: Our results show that the epidemic on the Isle of Wight was controlled quickly and effectively after the launch of Test and Trace. Our findings highlight the need for further research to determine the causes of the reduction in the spread of the disease, as these could be translated into local and national non-pharmaceutical intervention strategies in the period before a treatment or vaccination for COVID-19 becomes available. Funding: Li Ka Shing Foundation and UK Economic and Social Research Council.