The Microalgal Diatoxanthin Inflects the Cytokine Storm in SARS-CoV-2 Stimulated ACE2 Overexpressing Lung Cells

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Abstract

Contact between SARS-CoV-2 and human lung cells involves the viral spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor on epithelial cells, the latter being strongly involved in the regulation of inflammation as well as blood pressure homeostasis. SARS-CoV-2 infection is characterized by a strong inflammatory response defined as a “cytokine storm”. Among recent therapeutic approaches against SARS-CoV-2 targeting the dramatic inflammatory reaction, some natural products are promising. Diatoms are microalgae able to produce bioactive secondary metabolites, such as the xanthophyll diatoxanthin (Dt). The aim of this study is to demonstrate the anti-inflammatory effects of Dt on the A549-hACE2 lung cell line, exploring its interaction with the ACE2 receptor, as well as depicting its role in inhibiting a cytokine storm induced by the SARS-CoV-2 spike glycoprotein. Results showed that Dt enhanced the cell metabolism, e.g., the percent of metabolically active cells, as well as the ACE2 enzymatic activity. Moreover, Dt strongly affected the response of the SARS-CoV-2 spike glycoprotein-exposed A549-hACE2 cells in decreasing the interleukin-6 production and increasing the interleukin-10 release. Moreover, Dt upregulated genes encoding for the interferon pathway related to antiviral defense and enhanced proteins belonging to the innate immunity response. The potential interest of Dt as a new therapeutic agent in the treatment and/or prevention of the severe inflammatory syndrome related to SARS-CoV-2 infection is postulated.

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UCSF Chimera--a visualization system for exploratory research and analysis.

Eric F. Pettersen, Thomas Goddard, Conrad Huang … (2004)

The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.

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AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

Oleg Trott, Arthur Olson (2010)

AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.

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The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity

Qianqian Li, Jiajing Wu, Jianhui Nie … (2020)

Summary The spike protein of SARS-CoV-2 has been undergoing mutations and is highly glycosylated. It is critically important to investigate the biological significance of these mutations. Here we investigated 80 variants and 26 glycosylation site modifications for the infectivity and reactivity to a panel of neutralizing antibodies and sera from convalescent patients. D614G, along with several variants containing both D614G and another amino acid change, were significantly more infectious. Most variants with amino acid change at receptor binding domain were less infectious but variants including A475V, L452R, V483A and F490L became resistant to some neutralizing antibodies. Moreover, the majority of glycosylation deletions were less infectious whilst deletion of both N331 and N343 glycosylation drastically reduced infectivity, revealing the importance of glycosylation for viral infectivity. Interestingly, N234Q was markedly resistant to neutralizing antibodies, whereas N165Q became more sensitive. These findings could be of value in the development of vaccine and therapeutic antibodies.