Dr. Harvey Pollard and colleagues in their recent paper found that cardiac glycoside drugs like ouabain and digitoxin not only inhibit ACE2 binding to SARS-CoV-2 but also can block penetration of SARS-CoV-2 virus into human lungs cells.
For the SARS-CoV-2 virus to infect a target cell, the Receptor Binding Domain (RBD) on the viral Spike protein must bind to the receptor protein ACE2 on the cell surface. However, fully understanding the factors controlling this binding process is only at an early stage.
Now, Dr. Harvey Pollard and colleagues hypothesized that cardiac glycoside drugs such as ouabain, digitoxin, and digoxin might block the binding reaction between human receptor ACE2 and the Spike (S) protein, and thus block viral penetration into human lung cells. They also tested this hypothesis by developing a biochemical assay for ACE2:Spike binding, and tested cardiac glycosides as inhibitors of binding.
They found that, ACE2 binds with positive cooperatively to Receptor Binding Domain (RBD) protiens. They also found that mutations in the RBD, specifically Mink [Y453F] and UK [N501Y], significantly increased ACE2 binding affinity, while the S.Africa [E484K] mutation trended towards reduction in ACE2 binding affinity.
In addition, they also validated a previous finding that the [D614G] mutation, on a part of the spike S1 protein outside of the RBD, also reduced ACE2 binding affinity to the RBD. Thus the effect of a mutation that enhances infectivity need not necessarily increase the affinity of ACE2 for the RBD.
Furthermore, they measured ACE2 binding to the RBD protein in the presence of digitoxin, digoxin and ouabain, in order to test the ability of cardiac glycosides to inhibit ACE2 binding to the RBD protein. They found evidence that ACE2 binding in the presence of these drugs is reduced significantly. They also found that, out of 3 tested drugs, ouabain most potently block viral penetration into human lung cells, likely at a very early stage of the entry process. It is followed by digitoxin. But, digoxin was unable to block SARS-CoV-2 Spike pseudotyped virus penetration into human lung cells.
Finally, they suggested that, these drugs are widely available, and are clinically safe for those with normal hearts, so these inexpensive drugs could be repurposed for anti-COVID-19 therapy.
Reference: Hung Caohuy, Ofer Eidelman, Tinghua Chen, Qingfeng Yang, Alakesh Bera, Nathan Walton, Harvey B. Pollard, “Common cardiac medications potently inhibit ACE2 binding to the SARS-CoV-2 Spike, and block virus penetration into human lung cells”, bioRxiv 2021.06.02.446343; doi: https://doi.org/10.1101/2021.06.02.446343
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