Should you consume the quinine?

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Last week I was tagged in a video of a chiropractor touting the consumption of Schweppes tonic water and zinc supplements as the best way to armour ourselves against the novel coronavirus, SARS-CoV-2, that causes COVID-19. He cited reports of a doctor’s success in treating COVID-19 patients with hydroxychloroquine and zinc. This is no novel procedure, many physicians across the globe are turning to hydroxychloroquine and chloroquine as one of many pharmacological interventions in the fight against this new Severe Acute Respiratory Syndrome virus. But this chiropractor said we should get our hands on some Schweppes because it has HUGE amounts of quinine—a very similar agent to hydroxychloroquine and chloroquine.

His Facebook live got me thinking...

Why are we using these substances to treat COVID-19?

My thoughts transported me back to the summer of 2015, sheltered from the sweltering heat of a Tuscan sun and curled up with a book for my Historical Perspectives of Chemistry class. The book was Napoleon’s Buttons: How 17 Molecules Changed History. The chapter was 17: Quinine.

Quinine has been used as a medical treatment for centuries. It’s naturally derived from the bark of the Cinchona tree, a plant indigenous to the Andes region of South America. Natives of the region used the bark to treat fevers and nicknamed the plant the “Fever Tree” (later giving name to the very popular premium tonic water brand).

Quinine’s reputation as a treatment for malaria gained traction during Colonization. In the 1800s, British troops stationed in India began to consume quinine to prevent contracting the disease, but the substance was so bitter that they required a spoonful of sugar (and some water) to help the medicine go down. Thus, the first tonic water was created. And because all soldiers kept rations of gin on them (...don't you?), their daily medicinal cocktails became the first recorded “G&T” happy hour in history.

Soon the demand for quinine exceeded the rate of sustainable plant extraction, and a way to synthesise the compound chemically became necessary. In 1943, as a wartime effort, the US launched an extensive antimalarial research campaign in which thousands of compounds were tested. Chloroquine, first synthesised in 1934 by Hans Andersag at the Bayer company, won most promising. However, chloroquine, as with quinine, presented many serious side effects. Shortly after, in the 1950’s, a hydroxyl group—or an oxygen molecule bonded to a hydrogen molecule—was added to the compound, creating hydroxychloroquine (HCQ), thereby increasing the solubility of the drug and lowering its toxicity.

Unfortunately, by 1980 most strains of the malaria-causing parasite became resistant to chloroquine and HCQ. Other forms of antimalarials have since been developed with much success, but quinine, chloroquine, and HCQ are still in play today.

How exactly do these drugs works against Malaria?

And how did some species of the parasite become resistant?

To start, when a human becomes infected, the parasite firsts journeys to the liver where it hijacks liver cells to reproduce. Once the baby parasites mature, they burst into the bloodstream where they go on to hijack red blood cells.

Parasites have a stomach of sorts. It’s a single structure called a food vacuole. And the food of choice for malaria-causing parasites is hemoglobin—the stuff in red blood cells that is largely responsible for giving blood its red colour. But more importantly, it's the stuff responsible for transporting oxygen throughout the body.

When chloroquine is administered, for example, it enters the parasite and it concentrates in its food vacuole. It interferes with the vacuole’s breakdown of haemoglobin and without the “nutrients” from its foodstuffs, the parasite dies. Over time, however, these parasites developed functions to eject chloroquine from their vacuoles. And, the jig was up.

How did the drug get concentrated in the food vacuole to begin?

Researchers think it’s due to a phenomenon called ion-trapping.

We’ve all heard of the pH scale, right? It describes how acidic or basic a solution is on a scale from 0 to 14—0 being the most acidic, 7 being neutral, and 14 being the most basic (or alkaline). Ion-trapping essentially refers to the entrapment of acidic substances in basic mediums or basic substances in acidic mediums. Quinine, chloroquine and HCQ are all bases. I know this because I looked it up on Google....

It’s also reasonable to assume that quinine is a base because it’s what makes tonic water taste bitter. Acids taste sour. Bases taste bitter.

More specifically, these quinine-related compounds are considered weak bases because when reacted with water, they don’t completely dissociate, which means they don’t engage in proper social distancing….

No, actually, it means they don’t completely ionize, meaning most of the molecules in the solution are left unreacted and uncharged. This makes the compound closer to the pH of water which is around 7. This also makes it closer to the pH of blood and many other tissues—hovering just above 7—which allows these drugs to move throughout the body passively, as the cell membrane is more permeable to non-charged or non-ionised molecules.

It is important to note that, overall, the space inside the cell is slightly more acidic than the space outside the cell. However, specific structures inside the cell are way more acidic, and this pertains to both human and parasitic cells. In fact, the pH of a food vacuole in a parasite is around 4.5.

But when a basic, non-ionised molecule crosses the cell membrane, into the cell’s cytoplasm, and into an acidic organelle like a food vacuole, it does become charged. Once it’s charged, it can no longer go back through the membrane passively. This is how basic molecules accumulate in an acidic medium. In other words, this is how a basic drug like chloroquine can accumulate in a parasite's acidic parts, ultimately resulting in its death.

As I mentioned earlier, the food vacuole is kinda sorta like the parasite’s stomach. If you'd like a parallel, you can think of your own stomach. The human stomach secretes a mixture of acids with a pH between 1 and 3 that are crucial for breaking down the food we eat. Now say you want to inhibit the action of this acid because it’s going haywire—you have heartburn or acid reflux. So you reach for some TUMS (calcium carbonate) or Alkaseltzer (sodium bicarbonate). Your indigestion is neutralised because you fought an acid with a base.

In the meantime, chloroquine and HCQ have seen a new life treatment options for autoimmune diseases and HIV and cancer.

But why?

If chloroquine and HCQ work to kill a parasite, how do they work on viruses or the human body? Well, the exact mechanism of their action has yet to be elucidated. That’s right, folks, after hundreds of years of use and prescription, we still don’t know why these particular alkaline compounds work. We only have theories. And the same is now true for the use of quinine, chloroquine, and HCQ in the fight against COVID-19.

The following theories are what I’ve gathered from the research that’s already out there. Keep in mind, most of the knowledge we’ve gained about these drugs is from testing done in vitro, meaning in a test tube or a petri dish, not within a living organism.

As there is a lot of hype around chloroquine and HCQ (for example, in any of Trump’s recent press talks...), I expect more research to be churned out soon. And in the spirit of science, I expect everything in this article to be wrong by the time I post it.

Kidding...kinda.

But I read this quote in TIME magazine that read:

“Two of the most widely felt symptoms of the coronavirus are uncertainty and confusion. Part of this is about jargon. A doctor can make bad news even more alarming by using scientific terms that the patient [and might I add, public] doesn’t understand.”

So while I’m not a medical doctor (...I just sold my unopened MCAT study books from 2015...) or a scientist or a first responder on the frontlines, I do have some background in biomedical research, and I thought I would use my quaran-time to distil some of this jargon down. I’ll try to keep theory simple, but if I’ve made any errors in understanding, please bring that to my attention (even if it will doubtlessly hurt my ego--I'm a Leo).

I’ll take you through how the virus might operate in human cells and how Chloroquine might operate against it.

We start at the surface: The Cell Membrane

Although we refer to the virus that lends itself to our current global pandemic the “coronavirus,” it actually belongs to an entire family of viruses termed “coronavirus”. The surface of these coronaviruses contain projections called Spike or S-proteins. These projections give the virus the appearance of a crown. In fact, the scientists who first identified coronaviruses back in 1968 thought the magnified microbe reminded them of the sun’s corona, the crown-like ring of gasses that surrounds the sun and can be viewed during a solar eclipse.

Although it’s likely that the scientists followed the Latin tradition of naming ("coronum"), simply "corona" means crown in Spanish. It’s no wonder the logo for the Mexican-produced Corona beer brand is a crown; more specifically, it’s the crown that sits atop The Church of Our Lady of Guadalupe in Puerto Vallarta, Mexico.

Corona beer also sits atop very large shelves at the Puerto Vallarta Wal-Mart just steps away from its cruise terminal.

Anyway, the spike protein is the virus’s key to gain entry into the cell.

So, where's the door?

The door is called the ACE2 receptor, or angiotensin converting enzyme-type II receptor.

(I'll color-code to help you here.)

Angiotensin describes four hormones that are responsible for the narrowing and widening of blood vessels. Angiotensin-I causes vasodilation and angiotensin-II causes vasoconstriction. The ACE enzyme converts angiotensin-I into angiotensin-II, resulting in elevated blood pressure. ACE2 converts angiotensin-II back into angiotensin-I, resulting in lowered blood pressure.

You may have heard of something called an ACE-inhibitor. This is a class of medications usually prescribed to individuals with high blood pressure because if you inhibit the conversion of angiotensin-I to angiotensin-II, your blood vessels and resultant blood pressure can just, relax.

Who needs some of that right now?

Back to the door. ACE2 is present on the surfaces of artery, heart, kidney, and intestinal cells, but not surprisingly, it’s super concentrated in a type of cell in the alveoli—ya know, the little tiny bean bags in your lungs responsible for gas exchange.

Once the spike protein locks onto ACE2, it’s in!

Is it really that simple?

Scientists believe the door first needs to reveal a lock for the virus’s key to fit into.

We know that both the spike protein and the ACE2 receptor are proteins that are highly glycosylated. Glycosylation refers to the process of attaching a carbohydrate group, or a glycan, to a protein. What results from this process is a change in the shape of the protein, and for lack of a mechanism, we’ll just say this conformational change allows the virus to properly bind to the host cell. But where do the proteins get this sugary shape-shifting chain? Um, where any resident would get its sugar...from its neighbour.

That’s right, next door to the ACE2 receptor on the cell membrane is sialic acid, a simple sugar that dangles off the end of more complex sugars and is thought to contribute properties that help lubricate our body's airways. So, either the spike protein or ACE2 grabs some sugar and now we’re cooking.

But you know what also likes sugar? (Me.)

Chloroquine. Recent research posits that chloroquine also binds to sialic acid, disrupts glycosylation, and prevents proper binding of the virus.

The End.

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...or is it?

Say chloroquine didn’t stop the virus there….

What grants the 2002 coronavirus (SARS-CoV) entry into a cell isn’t a conformational change but a cleavage of the spike protein.

We know that proteins are chains of other molecules called amino acids. The sequence of a protein’s amino acids encodes what the protein is and what it does, but sometimes a protein isn’t active until this chain broken—much like a glow stick doesn’t glow until it’s broken. Along the sequence of the spike protein is a site for yet another protein called TMPRSS2 to come in and break the chain.

Again, we still don’t know the exact mechanism of entry, we only know that it sure as heck enters!

So viral parts are squirted into the cell. They’re taken in by a structure made up of the cell’s own membrane called an endosome in a process called endocytosis. Endosomes are the mail people. They sort and deliver internalised material to other places in the cell. On its journey into the interior of the cell, the endosome matures. It shifts from an early endosome to a late endosome to a lysosome. With each stage of development, the pH inside the vesicle decreases from about 6.5 to 4.5. The acidification of this vesicle has been shown to induce changes in the resident viral particles that allow them to secretly escape into the cell cytoplasm where it can then set up its copy shop.

You remember what other cell structure had a pH of 4.5? Yup, that food vacuole in the parasite. And what did we do to that vacuole to curb its haemoglobin cravings? Fed it chloroquine. The thought is the same here, if you give chloroquine to a virus-infected cell, it will interfere with the acidification of the lysosomes and stop the virus before it even thinks about sneaking out of the house.

The End.

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...or is it?!

Okay, say chloroquine didn’t even stop the virus there. Now what?

After the viral parts make their great escape, they need to find a place to raid.

We’ll cut straight to it. Autophagy is the cell’s means of cannibalism. No really, autophagy literally means self-eat. It’s a process in which damaged proteins and organelles within the cell are engulfed by a double-membraned vesicle and disposed of without having to kill the entire cell. It’s also handy when a cell needs to rid itself of a foreign invader.

Much like endocytosis, autophagy begins with the formation of a nascent phagophore or “isolation membrane"(...I think we can all relate). This phagophore matures into an autophagosome which then fuses with our super-duper acidic lysosome to form an autolysosome. It is here that the particles in the autophagosome are digested by the enzymes in the lysosome, and poof.

Coronaviruses, however, learned how to usurp this pathway so that they don’t go poof, but instead, they trick the double-membraned vesicle into providing them all the raw materials they need to construct their spawn.

Enter chloroquine--which we already know affects the pH in lysosomes.

If the lysosomes can’t do their whole digesting and garbage-disposaling, then autophagasomes can’t fuse to the lysosomes. This leads to a build-up of debris within the cell. The only option a cell has now is to kill itself in a different self-sacrificing process called apoptosis. No cell to infect, means no infection.

The End.

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…or is it?!?

Research shows that although the autophagy pathway is initiated in coronavirus infection, it isn’t solely required for its success, meaning it probably has a different hideout for its replication, like the Endoplasmic Reticulum or Golgi body--other double-membraned organelles.

So now what?

A main reason chloroquine has been used to control autoimmune diseases is because it has documented immunomodulatory effects. This is just a fancy way of saying it modulates the immune system. How? Well it could be a by-product of the mechanisms we’ve already discussed.

All of those processes or structures are instrumental to cell signalling. Cell signalling describes how cells interact with each other, and it’s an important phenomenon when considering how the cells and proteins of the immune system are recruited to fight an infection.

First we discussed the activation of the spike protein-ACE2 receptor complex. The process responsible this activation, be it glycosylation or cleavage, initiates cell signalling. This is where the proteins say:

“Houston, we have a touchdown.”

But more specific to the touchdown of viral pathogens is a receiver called the Toll-like receptor. These proteins are named not because they look like tolls but because they reminded the scientist who discovered them of the toll gene found in flies. The scientist who discovered toll genes in flies was German, and toll means “great” in German.

And these Toll-like receptors—or TLRs—are great. There are ten identified types in humans that are found along the cell membrane AND on the surface of endosomes. Each type has its own unique way of recognising Pathogen Associated Molecular Patterns or “PAMPs”…but we’ll just call them viral parts.

TLR 3, 7, 8, and 9 recognize viral parts on the endosomes. TLR7 in particular uniquely recognises viral parts through its sense of single-stranded RNA.

This is significant because coronaviruses are positive-sense (+) single-stranded RNA viruses, meaning their genetic material, the only thing that gives them an identity, is a single strand of nucleotides that function a lot like our body’s own messenger RNA (...see how our body might confuse the two?).

Messenger RNA is the stuff that directly translates a portion of our genes into the proteins it encodes for (with the help of ribosomes and transfer RNA, of course).

Once a coronavirus is recognised by TLR7, or any of its sibling TLRs, it activates the immune system bat signal (...that’s funny because this is a bat coronavirus...) and it beckons (in no particular order) to macrophages and cytokines and neutrophils and T-cells and B-cells and all those other buzzwords I’m certain you’ve heard in recent news reports that "it’s time to fight."

Autophagy, as we’ve also discussed, can present viral parts, and more specifically, viral RNA, to TLR7 in the endosomes to amplify the production of cytokines even further.

Cytokines (n.): the wireless network (signals) that connects you and your pals (other cells) during quarantine.

The actual mechanism of signal shuttling between TLRs and endosomes is super complex...go figure. But what we can gather is that if chloroquine interferes with glycosylation and/or endocytosis and/or autophagy, it most likely interferes with cell signalling.

Thus, chloroquine quells cytokine production and potentially puts a halt to the cytokine storm that unfortunately spirals some severely-infected individuals into multiple-system organ failure. In this instance, chloroquine isn’t combating the virus, it’s abating the body’s own immune system.

Now, I’m not going to say “The End” because there is one more action of chloroquine that brings us back to the beginning of our story when our beloved chiropractor told us to consume copious amounts of quinine and zinc.

If the virus succeeds in setting up its copy shop, it will use an enzyme called RNA-dependent RNA polymerase to make more of its genetic code leading to more viruses. Zinc is known to inhibit this replication. Zinc is a charged ion. If you remember back to earlier in this post, the cell membrane is not as accommodating to ionised particles. So if zinc was to enter the cell, it would need some help from a transporter: And ionophore.

When looking at chloroquine as a potential cancer treatment, a group of researchers inadvertently found that chloroquine is a zinc ionophore. Chloroquine sensitizes cells, shuttles zinc into the cytoplasm, and then zinc can do its inhibiting. Not only so, but the addition of zinc also enhances chloroquine’s inhibiting ability, leading to more effective, infected-cell deaths.

So, we SHOULD be consuming the quinine for medical purposes?

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NO.

While quinine, chloroquine, and HCQ are all related, they’re NOT THE SAME.

Quinine and chloroquine in particular have a laundry list of side effects and contraindications and adverse reactions with other drugs. Quinine can be eliminated from the body within 18 hours but chloroquine may take weeks to evacuate. Clinicians don’t even know the exact minimum dose for efficacy.

...150mg a day? ...200? ...400? ...800?!

And do ya wanna know how HUGE the amount of quinine is in Schweppes tonic water? 67.9mg per LITER. The FDA prohibits any tonic water to contain more than 83mg per liter. You’d have to drink well over TWO liters of tonic water a day to even touch the proposed therapeutic dose.

I know that while we’re in isolation you probably have steady access to a toilet (and a mountainous hoard of toilet paper); but even if this method did work, you’d probably be confronted with a gnarly skin rash before you’d be immune to COVID-19. (Just look up fixed drug eruption secondary to quinine consumption...yikes.)

Additionally, in a study that compared the preventative effects of quinine-related drugs, only HCQ significantly aided cells in warding off the virus, not quinine, not chloroquine. And because most chloroquine resistance in parasites occurred in areas of high transmission where people received the drug prophylactically, I’d be worried about this virus developing resistance before we even had the chance to see what works long-term…or what the virus even IS.

So no, don't consume quinine.

...unless it’s with gin and it’s for the purposes of emotional healing....

Except, maybe don’t do that either. Recent research suggests that this novel virus suppresses interferons as well. Interferons are the first cytokines that are deployed after the virus is recognized at a TLR site. They are named such because they literally interfere with viral specific replication, and they go on to active hundreds of other immune effectors. But if they’re suppressed, then the rest of our immune fighters aren’t deployed in a timely manner. This probably accounts for why so many people present as asymptomatic or mildly-symptomatic until a cytokine storm threatens their existence.

So if the virus has figured out a way to weaken your innate immune system, your best bet in a preventative measure would be to not weaken your system with alcohol.

Hey, you know what’s also a great preventative measure? Washing your hands.

Just like the fatty lipid bilayer that contains a virus, soap is made up of amphiphilic molecules. Amphiphilic translates to "both-loving", meaning one side loves water and one side loves fats. When soap is introduced to a virus, its fat-loving parts weasel their way into the virus’s fat-loving parts, breaking it apart and making it soluble in water. (I wish soap broke up my fat-loving parts.…) But this process is only complete after 20 seconds of soap application.

To recap:

What should you do?

Stay home. Exercise. Eat your vegetables. Drink water. Soak up some Vitamin D. If you’re a baller and you have a sauna, sit in your sauna. (Strategic application of heat and cold therapies is shown to reduce cytokine storms and bolster the innate immune system.) Thank the medical practitioners, first responders, and scientific researchers who are working tirelessly to ensure our safety. And, wash. your. hands.

What should you not do?

Drink two liters of Schweppes.