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A story of chloroquine and zinc against Covid-19

Today we're going to learn how chloroquine and zinc helps in the fight against COVID-19. 

Obviously, India is at war with the virus as everyone else in the world. Looking at the images that we see from the media in European countries, their methods look a little more draconian than in other places maybe. This one, also, they're doing way more testing than other countries. Thereby they identify cases that would be missed in other countries. So the denominator in that case fatality rate calculation is obviously larger than in other countries. But is that the whole story? What else are they doing differently? 
We've looked into it a bit deeper and we found that there's actually a COVID-19 central clinical task force composed of physicians and experts treating the confirmed patients across the nation. They recently held their sixth video conference and agreed on some very interesting treatment principles for patients with COVID-19. On this page, we can find a description of their recommendations. They recommend that patients should either receive Kaletra, which is a combination of lopinavir and ritonavir, or chloroquine 500 milligrams orally per day. In this consensus document from China, we can also see that they recommend chloroquine. At a different dose, but still the same drug. What's up here? So why does chloroquine seem to be efficient against SARS-KoV-2? In order to understand that we need to review a little bit of molecular biology. In the cell inside the nucleus we have DNA in a process called transcription. DNA is transcribed to create RNA. RNA then leaves the nucleus, goes into the cytoplasm, and there it's being modified. There's a A-A- A tail, and a five-prime cap that's being added, and this signals to the ribosomes that this RNA is ready for creating a protein. The ribosome moves from the five-prime cap to the A-A-A tail in a process called translation – whereby a protein is generated. Now what happens when a virus infects the cell?

This is SARS-KoV-2, it has a lipid bilayer just like the cell, but it also has various proteins attached to it and the big fat piece of RNA inside of it. These are the various proteins of the virus. This one here is called S -protein or spike protein. The virus uses this protein in order to attach to the ACE two receptor. The virus then enters the cell and releases its RNA into the cytoplasm of the cell. Inside the cell, this strand of RNA also has a five-prime cap and an A-A-A tail, and guess what? The host ribosomes attach to this piece of RNA and translate it, thereby creates a protein called RdRP or RNA-dependent RNA polymerase. Now this RdRP attaches to the A-A-A tail and copies it in this direction. This creates a negative version of this piece of RNA, which has the five-prime end on the other side and the three prime end on this side. Then the RDRP walks over to the other side again, copies the piece of RNA again, and what we end up with is an identical copy of the original viral genome. What's interesting is that the RNA-dependent RNA polymerase sometimes stops early and creates a shorter piece of RNA. Sometimes it stops here, sometimes it stops here and creates this piece of RNA. These pieces of RNA are called subgenomic RNAs, and again, the ribosomes, they think they have to translate these pieces of RNA. What happens then is you get these pieces of protein and those are the viral proteins that we've said previously. Now the replicated RNA and the viral proteins reassemble into a new virus, which is released from the cell and ready to infect another person. Now check out this - Zinc has been found to block the RNA-dependent RNA polymerase. This was reported in a paper titled "Zinc inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture". So here we have a molecule of zinc, but it's hard for it to enter the cell. So these scientists, they had to add a molecule called PT, which is an ionophore. Now, what does an ionophore do? Well, actually it makes the cell wall permeable for zinc. It grabs the zinc and pretty much carries it through the cell wall. And here's what they found, in their experiments. They use SARS-CoV the pathogen causing SARS. And they found that if they added more zinc to their experiments, less viral RNA was produced. So zinc could actually block viral reproduction. This RNA here is the product of the RdRP. Now, here's the explanation of why chloroquine might be effective in the treatment of COVID-19 because it is a zinc ionophore in and of itself. In the above said paper, they used ovarian cancer cells to prove that chloroquine enhanced zinc uptake by these cells. So what did they find? On the Y-Axis, you can see how much zinc they detected inside the cells here, and here. On the X-Axis are increasing concentrations of chloroquine or zinc. You can see that increasing doses of chloroquine cause increasing concentrations of zinc inside the cell. Similarly, more zinc was found inside the cell with increasing zinc concentrations outside the cell, and at each concentration of zinc, this effect was augmented by adding chloroquine to the experiment depicted by the black bars. Down here, they showed increasing levels of fluorescence zinc inside the cells. Here we have controls, almost no zinc. 

With 50 micromolar of zinc. A little more with 300 micromolar of chloroquine plus five micromolar of zinc. Even more, and much more. So obviously the addition of chloroquine had a really, really big effect on intracellular zinc, much more so than just adding zinc alone. This is a mechanism that how drugs act on the virus.
For the knowledge of Covid-19-

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