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The role of calcium ions in coronavirus infection

You may have heard that in SARS-CoV-2, the coronavirus spikes bind to a type of host cell receptors called ACE-2. But have you heard of research on the next step of virus entry, membrane fusion? Prof Susan Daniel from Cornell University has been investigating the virus entry mechanisms of SARS-CoV, with renewed importance given the emergence of the SARS-CoV-2.

There are two possible pathways for membrane fusion – the endocytosis pathway or the plasma membrane pathway. In the more direct latter pathway, the fusion peptide of the virus acts like a harpoon anchoring to the host cell membrane and allows the virus to release its genetic material into the host cell (refer to schematic below). 

Coronavirus membrane fusion

Coronavirus membrane fusion pathways. Image source: Prof Susan Daniel and team.

Daniel’s group is interested in inhibiting coronavirus fusion peptide's insertion into cell membrane. They noticed charged residues in the coronavirus genes and studied the role of calcium ions in membrane fusion. Firstly, with increased calcium ions in the cell culture buffer, the infectivity increased. To follow up, they used a membrane-permeable calcium chelator BAPTA-AM to increase the intracellular Ca2+ concentration and also found greater viral infectivity.

Ca2+ was found to favor two prerequisites for membrane fusion: alpha helix formation for fusion protein insertion, as well as lipid ordering in the host. Using isothermal calorimetry, it was found that two Ca2+ ions were required for every SARS-CoV fusion protein in an endothermic process. With the help of computational simulations, the binding sites of the fusion peptide with Ca2+ ions were predicted, giving surprising results!

Ca binding sites

Calcium ion binding sites of coronavirus fusion protein. Image source: Prof Susan Daniel and team.

Since the gene residues involved in membrane binding are largely conserved in different coronaviruses such as MERS-CoV and SARS-CoV-2, the same principle of calcium sensitivity could be used to inhibit SARS-CoV-2. With reducing Ca2+ in mind, the team sought to find possible drugs which may lower SARS-CoV-2 infectivity. The three CCB drugs are already FDA-approved for cardiac conditions. Vero-E6 kidney cells and Calu-3 lung cancer cells were exposed to the drugs and live coronavirus. While some of the CCB drugs show promise in reducing the infectivity, it’s still too early to gauge if they could be effective for coronavirus prevention and we are not encouraged to take those drugs without prescription. Further follow-up studies are still needed. 

By studying the biomolecular pathways of viruses, scientists have gained a better understanding of the infection mechanisms. Targeting the problem at its roots enabled us to narrow down on potential drug candidates.

Watch the recording of Fundamentals/Therapeutics: F.GI01.11: Live Keynote III & F.GI01.12: Live Panel Discussion III.

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