![]() ![]() Accordingly, the pinheads of externalized PS also face down. Blue horizontal lines represent a cellular membrane with the cell surface facing down. Orange arrows represent proteolytic activity, grey arrows show a transition between forms. Activated factors are labeled with an a, as in FXa. For simplicity, in this cartoon the letter F is omitted. Most proteins involved in coagulation are called factors and are labeled by Roman numerals, such as Factor X or FX (hence enzymes that process FX are tenases). Blood coagulation cascade is a network of proteases, their precursors, cofactors, cells, enzymes, feedbacks, and feedforwards whose complexity and still unresolved questions make this outline by necessity rudimentary, with the primary goal to illustrate where the proteins that require binding to externalized PS (phosphatidylserine) for activation are in the network. ![]() To evaluate this assumption let us consider how cell fusion and syncytia it produces might be involved in COVID-19.įigure 1: An outline of the blood coagulation cascade. This assumption, that the scramblase activity merely helped to identify the ion channel as a potential therapeutic target, reflects a common opinion that syncytia produced in the body by infectious viruses are inconsequential. However, Braga and colleagues have concluded that although PS externalization “is required for plasma membrane fusion, chloride secretion might have relevance in COVID-19 pathogenesis”. PS externalization is required for cell fusion in many systems, which explains why inhibiting a scramblase prevents the formation of spike-induced syncytia. One, a calcium-activated ion channel, regulates chloride secretion, while the other, a lipid scramblase, relocates phosphatidylserine (PS) to the cell surface in a process known as PS externalization. Recently, Braga and colleagues identified a set of already approved drugs that prevent spike-induced cell fusion and inhibit TMEM16F, a protein that has two activities. These syncytia have been attributed to the ability of spike, a protein encoded by SARS-CoV-2, to fuse cells to each other, and prompted a search for drugs that could prevent this cell fusion. ![]() A hallmark of severe COVID-19 is the abundance of syncytia, the products of fusion between two or more cells in the lungs of patients. ![]()
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