Metal-coding assisted serological multi-omics profiling deciphers the role of selenium in COVID-19 immunity.

Uncovering how host metal(loid)s mediate the immune response against invading pathogens is critical for better understanding the pathogenesis mechanism of infectious disease. Clinical data show that imbalance of host metal(loid)s is closely associated with the severity and mortality of COVID-19. However, it remains elusive how metal(loid)s, which are essential elements for all forms of life and closely associated with multiple diseases if dysregulated, are involved in COVID-19 pathophysiology and immunopathology. Herein, we built up a metal-coding assisted multiplexed serological metallome and immunoproteome profiling system to characterize the links of metallome with COVID-19 pathogenesis and immunity. We found distinct metallome features in COVID-19 patients compared with non-infected control subjects, which may serve as a biomarker for disease diagnosis. Moreover, we generated the first correlation network between the host metallome and immunity mediators, and unbiasedly uncovered a strong association of selenium with interleukin-10 (IL-10). Supplementation of selenium to immune cells resulted in enhanced IL-10 expression in B cells and reduced induction of proinflammatory cytokines in B and CD4+ T cells. The selenium-enhanced IL-10 production in B cells was confirmed to be attributable to the activation of ERK and Akt pathways. We further validated our cellular data in SARS-CoV-2-infected K18-hACE2 mice, and found that selenium supplementation alleviated SARS-CoV-2-induced lung damage characterized by decreased alveolar inflammatory infiltrates through restoration of virus-repressed selenoproteins to alleviate oxidative stress. Our approach can be readily extended to other diseases to understand how the host defends against invading pathogens through regulation of metallome.

In silico structure-based discovery of a SARS-CoV-2 main protease inhibitor.

The Coronavirus Disease 2019 (COVID-19) pandemic caused by the novel lineage B betacoroanvirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant mortality, morbidity, and socioeconomic disruptions worldwide. Effective antivirals are urgently needed for COVID-19. The main protease (Mpro) of SARS-CoV-2 is an attractive antiviral target because of its essential role in the cleavage of the viral polypeptide. In this study, we performed an in silico structure-based screening of a large chemical library to identify potential SARS-CoV-2 Mpro inhibitors. Among 8,820 compounds in the library, our screening identified trichostatin A, a histone deacetylase inhibitor and an antifungal compound, as an inhibitor of SARS-CoV-2 Mpro activity and replication. The half maximal effective concentration of trichostatin A against SARS-CoV-2 replication was 1.5 to 2.7µM, which was markedly below its 50% effective cytotoxic concentration (75.7µM) and peak serum concentration (132µM). Further drug compound optimization to develop more stable analogues with longer half-lives should be performed. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of SARS-CoV-2.

Xanthones from Swertia mussotii and their α-glycosidase inhibitory activities.

Two new xanthones, 1,8-dihydroxy-3-methoxyxanthone 7-O-[α-L-rhamnopyranosyl(1 → 2)-ß-D-glucopyranoside] (1) and 1,8- dihydroxy-3-methoxyxanthone 7-O-[α-L-rhamnopyranosyl(1 → 3)-α-L-rhamno-pyranosyl (1 → 2)-ß-D-xylopyranoside] (2), together with 26 known xanthones (3-28), were isolated from the aqueous ethanol extract of the traditional Chinese herb Swertia mussotii. Their structures were elucidated via spectroscopic analyses including 2D NMR. The inhibition of α-glucosidase by the isolated xanthones was evaluated by an in vitro high-throughput screening assay. Our results indicated that 1,3,5,8-tetrahydroxyxanthone is the best inhibitor with an IC50 value of 5.33 ± 0.09 µM, while the O-glycosylated xanthones were poor α-glycosidase inhibitors.

Antioxidant xanthones from Swertia mussotii, a high altitude plant.

Four new xanthones, 3,5,6,8-tetrahydroxyxanthone-1-C-ß-D-glucoside (1), 7-hydroxy-3,4,8-trimethoxyxanthone-1-O-(ß-D-glucoside) (2), 6-hydroxy-3,5-dimethoxyxanthone-1-O-(ß-D-glucoside) (3), 3,4,7,8-tetramethoxyxanthone-1-O-(ß-D-glucoside) (4), together with twenty-one known xanthones (5-25) were isolated from the ethanol aqueous extract of Swertia mussotii. Their structures were elucidated via spectroscopic analyses. Oxygen radical absorbance capacity of all the isolated xanthones was systematically evaluated by ORAC(FL) assay. Results disclose that all the tested xanthones display moderate to excellent antioxidant activity, where 1 is the most active compound and 13 is the least one. A preliminary structure-activity relationship is also discussed.