Hey everyone. Today we’re going to learn how we mightbe able to use chloroquine and zinc in thefight against COVID-19. But before we get started, I wouldlike to point out some numbers. These are the number of casesand deaths as of March 16th. I want to point you specificallyto the numbers of South Korea. There, we currently have 8,236 cases. And only 75 deaths. That’s incredibly low. That’s below 1%!What’s happening here?Why are they so good?As we learned in a previous video, casefatality rate can be calculated as numberof deaths divided bynumber of cases, times 100. However, this is not totally accuratebecause there are some cases here thathaven’t been cases for longenough in order to die yet. So this method probably underestimatesthe true case fatality rate. However, it’s still a good methodto compare the different countries. So what’s going on?Obviously, South Korea is at war withthe virus as everyone else in the world. Looking at the images that we see from themedia, their methods look a little moredraconian than in other places maybe. This one, also, they’re doing waymore testing than other countries. Thereby they identify cases thatwould be missed in other countries. So the denominator in that case fatalityrate calculation is obviously larger thanin other countries. But is that the whole story?What else are they doing differently?We’ve looked into it a bit deeper and wefound that there’s actually a COVID-19central clinical task force composedof physicians and experts treating theconfirmed patients across the nation. They recently held their sixth videoconference and agreed on some veryinteresting treatment principlesfor patients with COVID-19. On this page, we can find adescription of their recommendations. They recommend that patients should eitherreceive kaletra, which is a combination oflopinavir and ritonavir, or chloroquine500 milligrams orally per day. In this consensus document from China,we can also see that they recommendchloroquine. At a different dose,but still the same drug. What’s up here?So why does chloroquine seem tobe efficient against SARS-KoV-2. In order to understand that we need toreview a little bit of molecular biology. This is the cell. This is the cytoplasm. This is the nucleus. Inside the nucleus, we have DNAin a process called transcription. DNA is transcribed to create RNA. RNA then leaves the nucleus, goes into thecytoplasm, and there it’s being modified. There’s a A-A- A tail, and a five-primecap that’s being added, and this signalsto the ribosomes that this RNAis ready for creating a protein. The ribosome moves from the five-primecap to the A-A-A tail in a process calledtranslation – wherebya protein is generated. Now what happens when avirus infects the cell?This is SARS-KoV-2, it has a lipid bilayerjust like the cell, but it also hasvarious proteins attached to it andthe big fat piece of RNA inside of it. These are the variousproteins off the virus. This one here is calledS-protein or spike protein. The virus uses this protein in orderto attach to the ACE two receptor. The virus then enters the cell andreleases its RNA into the cytoplasm of thecell. Inside the cell, this strand of RNA alsohas a five-prime cap and a A-A-A tail, andguess what?The host ribosomes attach to this piece ofRNA and translates it, thereby creates aprotein called RdRP orRNA-dependent RNA polymerase. Now this RdRP attaches to the A-A-Atail and copies it in this direction. This creates a negative version of thispiece of RNA, which has the five-prime endon the other side and thethree prime end on this side. Then the RDRP walks over to the other sideagain, copies the piece of RNA again, andwhat we end up with is an identicalcopy of the original viral genome. What’s interesting is that theRNA-dependent RNA polymerase sometimesstops early and createsa shorter piece of RNA. Sometimes it stops here, sometimes itstops here and creates this piece of RNA. These pieces of RNA are called sub genomicRNAs, and again, the ribosomes, they thinkthey have to translatethese pieces of RNA. What happens then is you get thesepieces of protein and those are the viralproteins that we’ve seen previously. Now the replicated RNA and the viralproteins reassemble into a new virus,which is released from the celland ready to infect another person. Now check out this – Zinc has been foundto block the RNA-dependent RNA polymerase. Check out this paper titled “Zinc inhibitscoronavirus and arterivirus RNA polymeraseactivity in vitro and zinc ionophoresblock the replication of these viruses incell 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 amolecule called PT, which is an ionophore. Now, what does an ionophore do?Well, actually it makes thecell wall permeable for zinc. It grabs the zinc and pretty muchcarries it through the cell wall. And here’s what they found,in their experiments. They use SARS-CoV thepathogen causing SARS. And they found that if they added morezinc to their experiments, less viral RNAwas produced. So zinc could actuallyblock viral reproduction. This RNA here is the product of the RdRP. Now, here’s the explanation whychloroquine might be effective in thetreatment of COVID-19 because it isa zinc ionophore in and of itself. In this paper, they used ovarian cancercells to prove that chloroquine enhancedzinc uptake by these cells. So what did they find?On the Y-Axis, you can see how much zincthey detected inside the cells here, andhere. On the X-Axis are increasingconcentrations of chloroquine or zinc. You can see that increasing dosesof chloroquine cause increasingconcentrations of zinc inside the cell. Similarly, more zinc was found inside thecell with increasing zinc concentrationsoutside the cell and at each concentrationof zinc, this effect was augmented byadding chloroquine to the experimentdepicted by the black bars. Down here, they showed increasing levelsof fluorescence zinc inside the cells. Here we have controls, almost no zinc. With 50 micromolar of zinc. A little more with 300 micromolar ofchloroquine plus five micromolar of zinc. Even more, and much more. So obviously the addition of chloroquinehad a really, really big effect onintracellular zinc, much moreso than just adding zinc alone. That’s it for now. If you want to improve your understandingof epidemiology, make sure to register fora free Medmastery trial account andattend our Epidemiology Essentials Course. We’ve just opened it up to trialusers due to the huge demand. So stay safe and talk soon.