Chapter 43: Drugs for the Treatment of Viral Infections

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Hello and welcome back to The Deep Tive.

Today, we are shifting gears a little.

We are dimming the lights, putting a do not disturb sign on the door, and pouring a very, very large cup of coffee.

Ah, the classic signs of a last minute lecture.

It is indeed a last minute lecture.

And the monster on the desk today is chapter 43 of Brenner and Stevens Pharmacology, the sixth edition.

And the title is Deceptively Simple, Drugs for the Treatment of Viral Infections.

Deceptively is the right word.

It sounds straightforward, but then you open the pages and it is just,

it's a dense microscopic war zone.

It really is.

You've got these diagrams of replication cycles that look like, I don't know, subway maps from a city you've never been to.

The drug names.

It's like someone's filled a bag of Scrabble tiles on the floor.

Exactly.

And underneath all that complexity is this, this pressure that this stuff is incredibly important, clinically vital.

Right.

Because this isn't some obscure corner of pharmacology that only a few specialists see.

Viruses are.

Yeah.

Well, they're everywhere.

Everyone deals with them.

From the cold sore on your lip to the flu that knocks you out for a week to, you know, much more serious life altering diagnoses like HIV and hepatitis C.

Exactly.

So our mission today is to take this chapter and just decode it.

We're not just going to read the bolded terms.

No, we're going to crawl right inside the cell, look at the machinery and figure out how these tiny molecules actually work.

We're going to tackle the mechanisms, the kinase trick, the alphabet soup that is heart therapy, and the, well, the revolution in hepatitis C treatment.

So if you're a student listening to this on the way to a big exam, or maybe you're just someone who wants to understand why your doctor prescribed that specific pill,

stick with us.

We are going to make this make sense.

But before we even touch a single drug molecule, the text opens with a bit of a philosophical curve ball.

It does.

It poses that question that biologists have been arguing about for, what, a century.

Are viruses alive?

It really feels like a trick question, doesn't it?

It does.

But it's not really.

The text defines them with this great phrase, obligate intracellular parasites.

Which is just a very fancy way of saying they're moochers.

Total freeloaders.

I mean, think about it.

A virus is essentially just a little scrap of genetic material RNA or DNA wrapped up in a protein coat.

That's it.

So if you just put one on a table, it just sits there.

It doesn't breathe.

It doesn't eat.

It doesn't move.

It's inert.

You could argue it's just a piece of complex chemistry, not really biology.

Until it gets inside a host.

Until it gets inside you.

Right.

The second it gets inside one of our cells, it sheds that protein coat and it hijacks the whole factory.

It seizes control of your metabolic pathways, your energy, your ribosomes, your enzymes.

And it forces them to stop making human stuff and start making virus stuff.

And that right there brings us to the fundamental problem of antiviral pharmacology.

The book highlights this on page one.

If the virus is using my factory, my workers,

my energy,

how do I bomb the virus without blowing up my own factory?

That is the selective toxicity challenge in a nutshell.

I mean, think about antibiotics for a second.

Bacteria are prokaryotes.

They're basically aliens compared to our eukaryotic cells.

They are parts we don't have.

Exactly.

They have cell walls.

We don't.

They have different ribosomes.

So we can design a drug that smashes a bacterial cell wall and it just bounces right off a human cell because there's no target there.

It's relatively speaking easy.

But with the virus, the bad guy is inside the house.

The virus is the house in a way.

It's using your own enzymes to build itself.

So finding a drug that kills the virus but spares the host is incredibly difficult.

We have to look for the tiniest, most subtle differences.

Like a secret weakness.

Secret weakness.

Maybe the virus brings one specific enzyme with it that our cells don't have, or maybe it's polymerous.

The enzyme that copies its DNA works just a little bit differently than ours.

We're looking for the needle in the haystack.

We are.

We're looking for that one little lever we can pull that shuts down the viral assembly line but keeps the human one running.

And if you look at the scope of this chapter, herpes, HIV, influenza, hepatitis, the vast majority of our successes come from targeting one specific process.

And that is?

Nucleic acid synthesis.

Just stopping the virus from copying its genetic blueprint.

If it can't copy its code, it can't reproduce.

Game over.

Okay, that makes sense.

So let's get into the specific battlefields.

The chapter kicks off with herpes virus infections.

Right.

And we should probably be clear about the cast of characters here because the word herpes covers a lot of ground.

It does.

The text really focuses on three main bad guys in this family.

First, you have HSV herpes simplex virus.

That's yeah, this is what causes herpes labialis, that's cold sores, and also herpes genitalis.

Then we have VZV?

Viracella zoster virus.

That's the one that gives you chicken pox when you're a kid, and then it goes dormant.

It hides in your nerves for 50 years.

And comes roaring back as shingles when you're older.

Exactly.

When you're stressed or your immune system is down, it reactivates along a nerve route.

And the third one,

it's CMV, right?

CMV, cytomegalovirus.

This one is kind of silent lurker.

In a healthy person, what the text calls immunocompetent, it usually causes no symptoms at all.

Or maybe a mild monolike illness.

You probably wouldn't even know you had it.

But if your immune system is compromised.

Then it's an absolute nightmare.

In AIDS patients or transplant recipients, CMV can attack the retina causing retinitis, the colon causing colitis, or the esophagus.

It's a major cause of morbidity and mortality in that population.

Okay, so those are targets.

HSV, VZV, CMV.

Now let's talk about the weapons.

The chapter introduces us to the nucleoside analogs.

And the superstar, the prototype drug here, is a cyclover.

Right.

So help me visualize this.

What exactly is a nucleoside analog?

Okay, imagine you're a construction worker building a wall of DNA.

You have a big pile of bricks.

Those bricks are the natural nucleosides, guanosine, adenosine, thymidine that your body uses to build DNA.

The basic building block.

The A decoy.

A perfect decoy.

It looks almost identical to a real brick.

So the enzyme that's building the DNA wall, the DNA polymerase, it reaches into the pile, grabs this fake brick, and tries to put it into the wall.

And it's not a real brick, so something goes wrong.

Something goes very wrong.

And this is where the mechanism gets so incredibly elegant.

The text details what we can call the kinase trick.

This is the whole key to that selective toxicity we were just talking about.

Okay, the kinase trick.

Here's the thing.

A cyclover in the pill you swallow is totally inactive.

It's a dud.

It does nothing.

So I swallow the pill, it gets into my bloodstream, it enters all my cells, and nothing happens.

In a healthy, uninfected cell, yes.

It just floats around and eventually gets washed out.

Because to become active, to become a brick that can be used by the builder, it needs to be phosphorylated.

It needs to have three phosphate groups tacked onto it.

You can think of them like three security clearance stamps you need to get into a high security building.

Stamp one, stamp two, stamp three.

Okay, got it.

Three stamps.

Now, here is the catch.

The human enzyme that gives out the first stamp, our cellular kinase, it looks at a cyclover and says, nope, I don't know you.

You're not a real guanosine brick.

Yeah.

And it refuses to stamp it.

So in a healthy cell, a cyclover never gets that crucial first stamp.

It stays inactive.

Precisely.

But the herpes virus is, well, it's arrogant.

It brings its own kinase enzyme with it into the cell.

It's called viral thymidine kinase.

And its enzyme is different.

It's different.

And it's sloppy.

The viral thymidine kinase looks at a cyclover and says, it looks close enough to a guanosine to me.

Here's your stamp.

Wait a minute.

So the virus itself is the one that activates the drug that's going to kill it.

That is the absolute beauty of it.

The virus literally signs its own death warrant.

That viral enzyme adds the first phosphate.

Once that first stamp is on, the drug is now disguised enough that our own human host enzymes are fooled.

They see the one phosphate and say, oh, okay, I can work with this.

And they add the second and third stamps.

So now we have a cyclover triphosphate.

It's fully armed and dangerous.

Fully armed.

And now we go to the DNA polymerase, the brick layer.

The viral DNA polymerase, which is much more sensitive to this than our own polymerase, it grabs this activated a cyclover and snaps it onto the end of the growing viral DNA chain.

And then it gets stuck because a cyclover has a fatal flaw in its design.

It's missing a specific chemical called the three prime hydroxyl group.

The three prime hydroxyl group.

Why does that matter?

So in our brick wall analogy, the three prime hydroxyl group is like the wet cement on top of the brick that lets the next brick stick to it.

A cyclover doesn't have that cement.

It's got a smooth flat top.

So the enzyme places the cyclover brick into the wall.

And then it reaches for the next brick to put on top, but there's nowhere for it to attach.

It just slides right off.

The chain is terminated.

The wall stops growing.

Chain termination.

It sounds so final.

It is.

The viral replication complex just freezes solid.

It's a dead end.

And because the drug was only activated in infected cells, thanks to that sloppy viral kinase, it leaves our healthy cells largely alone.

It's a beautiful piece of biochemical engineering.

It's incredibly elegant,

but the text does mention a practical problem with the cyclover.

It has to do with

pharmacokinetics.

Getting it into the body.

Right.

It has really poor oral bioavailability.

If you take in a cyclover pill, only about 22 % of the drug actually gets from your stomach into your bloodstream.

That's not much.

So you have to take a really big dose or take it very often.

You do.

Patients might have to take pills five times a day just to keep the drug levels high enough in their blood to work.

And that's a huge compliance nightmare.

I mean, who remembers to take a pill five times a day?

Not me.

So the chemist went back to the drawing board.

And they came up with a valiciclover.

If you look at the structure, it's just a cyclover with a little valine amino acid tag attached to it.

It's what we call a prodrug.

So it's inactive until the body processes it.

Exactly.

You swallow valiciclover.

Your gut has transporters that love that valine tag, so it absorbs it really, really well.

The bioavailability jumps from 22 % up to 55%.

That's a huge difference.

Massive.

And once it's in the blood, enzymes in the liver and intestine just chop off that valine tag and boom, you're left with pure acyclover.

So valiciclover is essentially just a high efficiency delivery truck for a cyclover.

That's a perfect way to put it.

And that improved delivery allows for maybe twice daily or even once daily dosing.

Much, much better for the patient.

Famsiclover is a similar idea.

It gets turned into Pensiclover and its bioavailability is even higher, around 80%.

Now, generally the text says these are pretty well tolerated drugs, but there's a specific warning, a big one, regarding intravenous acyclover.

What's going on there?

Crystalline nephrotoxicity.

This is a big deal.

Acyclovir is not very soluble in water and especially not in urine.

If you give a very high dose of acyclover through an IV and the patient is even a little bit dehydrated, the drug can actually precipitate out of the liquid.

It forms crystals right inside the kidney tubules.

It turns into like microscopic rocks inside your kidneys.

That's exactly what happens.

It acts like sandpaper.

It scrapes up the tubules and it can block the flow of urine entirely.

It causes an acute but usually reversible renal dysfunction.

So the clinical pearl for any student listening is?

If you are giving IV acyclover, you absolutely must hydrate the patient aggressively.

Give them lots of fluids.

Flush those kidneys out to keep the drug dissolved.

Got it.

Okay, so that handles HSV and VZV pretty well, but then the chapter pivots to CMV cytomegalovirus and it says acyclover is basically useless here.

Why is that?

It goes right back to our kinase trick.

CMV is a herpes virus, yes, but it doesn't have that specific viral thymidine kinase that's so good at activating a cyclover.

It has a different kinase gene called

UL97.

And that one isn't as sloppy.

It's much more discerning.

A cyclover just bounces right off.

It never gets that critical first phosphate stamp, so it never gets activated.

So against CMV, we need a different weapon.

We do, and that weapon is gantzoclovir.

Okay, gantzoclovir.

It sounds like a cyclover's meaner, tougher, older brother.

It kind of is.

Gantzoclovir is structurally different enough that the CMV kinase, that UL97 protein, will recognize it and will put that first phosphate group on.

So it works against CMV, where cyclover completely fails.

It's about a hundred times more active against CMV.

But I'm guessing there's a price to pay for that power.

The toxicity section for gantzoclovir in the book looks a lot scarier.

Much scarier.

You have to remember, the more potent we get, often the less selective we become.

Gantzoclovir inhibits the viral DNA polymerase, sure, but it also inhibits our own human DNA polymerase to some extent.

And it especially hits our most rapidly dividing cells.

Rapidly dividing cells.

We mean like in our bone marrow.

Exactly.

The number one major side effect is myelosuppression.

That's a shutdown of the bone marrow.

You get leukopenia, dangerously low white blood cells, and thrombocytopenia low platelets.

You can completely wipe out a patient's immune system while you're trying to save them from a virus.

So this is serious stuff.

It's why gantzoclovir is a black box warning drug.

You don't use this for simple cold sore.

You use it when CMV is threatening to blind an immunocompromised patient or destroy a transplanted organ.

And just like valiciclover, gantzoclovir has an oral pro -drug version.

It does.

Valgansiclovir, same concept.

Tack on aveline, get better absorption, and it turns into gantzoclovir in the blood.

Boost the bioavailability up to around 60%.

Now, evolution is always a threat in this world.

What happens when these viruses learn to beat our drugs?

What does resistance look like here?

Well, for the virus, it's a pretty simple calculation.

If the drug relies on a specific viral enzyme to be turned on, like that thymidine kinase, the easiest way for the virus to become resistant is to just mutate and start making that enzyme.

But doesn't the virus need that enzyme to survive?

You'd think so, but not always.

It can sometimes scavenge what it needs from the host cell's machinery.

So you end up with these thymidine kinase deficient mutant viruses,

and they are resistant to both acyclovir and gantzoclovir because the drugs never get activated.

The kinase trick fails.

So what do we do then when the first line of drugs doesn't work?

We have to bring in the heavy hitters.

We need a drug that either doesn't need the trick or that works by a completely different mechanism.

And that brings us to two drugs,

pseudophovir and foscarnate.

Okay, let's start with pseudophovir.

Pseudophovir is a nucleotide analog.

Notice the T in there.

Nucleotide, not nucleoside.

What's the difference?

It means it already has a phosphate group chemically attached to it.

It comes pre -stamped, if you will.

It doesn't need the viral kinase to give it that first stamp.

It completely bypasses step one.

Ah, so it works even if the virus has got rid of its kinase enzyme.

Exactly.

But, and there's always a but, it is incredibly nephrotoxic.

It's very, very hard on the kidneys.

So hard, in fact, that we often have to give it with a second drug, probenicid, just to protect the kidney tubules from damage.

And the other one, foscarnate.

The text calls this a pyrophosphate derivative, which sounds completely different.

Foscarnate is the odd one out.

It is not a nucleoside analog at all.

It doesn't pretend to be a brick.

Think of it more like a piece of chewing gum.

Chewing gum.

Yeah.

It binds to a totally different spot on the DNA polymerase enzyme, the pyrophosphate binding site, and it just jams the whole mechanism.

It physically blocks the enzyme, so it can't work.

It doesn't need any activation.

No activation required whatsoever.

It's ready to go right out of the bottle.

So it works on acyclovir -resistant HSV, ganciclovir -resistant CMV.

It's our backup plan when the kinase trick fails.

But, I sense another but coming.

Oh, it's a big one.

Foscarnate is a toxicity nightmare.

It causes renal impairment in a huge percentage of patients.

It can cause seizures, and it really messes with electrolytes.

It chelates divalent cations, so your calcium, phosphate, magnesium, and potassium levels go all over the place.

It can cause severe, life -threatening hypercalcemia.

So this is absolutely the drug you keep in the glass case that says break only in case of extreme emergency.

That is precisely what it is.

It's salvage therapy.

Before we close the book on herpes, the chapter mentions just a couple of topical agents.

Right.

Just to be complete, there's Pensaclova cream for cold sores.

It might shorten the duration by about half a day if you apply it constantly.

Mungus benefit.

Very modest.

And then there's Trifluridine.

This one's important for the eye.

It's used for herpetic carotid conjunctivitis.

It's a pyrimidine analog that gets incorporated into the viral DNA and messes it up.

It's far too toxic to put in your blood, but as an eye drop, it stays local and can save the patient's cornea.

Okay.

Let's take a deep breath.

We are moving from the herpes family to what is arguably the most complex and historically significant section of this entire chapter.

HIV.

The human immunodeficiency virus.

And the text starts this section with a really important piece of framing.

It talks about the transition of HIV from what was a universally fatal disease to what is now a chronic manageable condition.

And that right there is probably the single greatest achievement in the entire history of antiviral pharmacology, without question.

In the 1980s and early 90s, an HIV diagnosis was a death sentence.

Today, with proper adherence to medication, a person with HIV can have a near normal life expectancy.

And the strategy that made that incredible leap happen is heart.

H -A -A -R -T.

Highly active antiretroviral therapy.

The central dogma of all modern HIV treatment is this.

You never, ever use monotherapy.

You never use just one drug.

Why not?

Is the virus just that tough?

It's not that it's tough, it's that it's fast and incredibly sloppy.

HIV replicates billions of times a day and its key enzyme, reverse transcriptase, makes mistakes constantly.

And those mistakes are mutations.

Those mistakes are mutations.

So if you use just one drug to attack it, statistically, the virus will randomly produce a mutant that happens to be resistant to that one drug within a matter of weeks.

So it just evolves its way right out of the trap you set for it?

Instantly.

But if you hit it with three drugs, all with different mechanisms of action, all at the same time, the mathematical probability of a single virus particle spontaneously mutating to resist drug A, drug B, and drug C all at the exact same moment

is vanishingly small.

We trap the virus in a corner, it can't mutate its way out of.

Okay, so to understand the drugs, we have to understand the targets.

Think your 43 .2 in the text lays out the HIV life cycle.

It looks like a really complex heist operation.

Can you walk us through the steps?

Absolutely.

So picture the HIV variant, this little spiky ball floating up to one of your CD4 T cells, which is basically the command center of your immune system.

Step one is entry.

Get in the door.

Right.

The virus has to grab the door handle, which is the CD4 receptor, and then it has to unlock the deadbolt, which is a co receptor like CCR5.

Once it does that, it fuses its membrane with the cell's membrane and dumps its contents inside.

So now the viral RNA is inside our cell.

What's next?

Step two is reverse transcription.

This is the signature move of a retrovirus.

It takes its single stranded RNA genome and uses an enzyme it brought with it called reverse transcriptase to turn it into double stranded DNA.

It's writing its code backward into the language of the host.

Okay, so it makes a DNA copy of itself.

Correct.

Step three is integration.

That new viral DNA travels into the nucleus of our cell and another viral enzyme can it integrase acts like a pair of molecular scissors.

It cuts open our human DNA and pastes the viral DNA right into the middle of one of our chromosomes.

That is just terrifying.

It literally becomes a permanent part of your own genome.

It does, which is why it's so hard to cure.

From then on, whenever that cell divides, it copies the viral DNA along with its own.

Step four is transcription and translation.

Our cell's machinery now reads that inserted viral DNA, thinking it's its own, and starts churning out viral messenger RNA and viral proteins.

It becomes a virus factory.

And the viral parts come together at the cell membrane.

They bud off to form a new immature virus, and then a final enzyme, HIV protease, makes the final cuts to make the virus mature and infectious, ready to go attack the next cell.

Okay, we have the map of the heist.

Now let's look at the arsenal.

Class I, NRTIs, Nucleoside Reverse Transcriptase Inhibitors.

These are the OGs, the original gangsters of HIV therapy.

They are the Trojan horses.

Just like a cyclover, these are Nucleoside analogs, their fake DNA building block.

And they work the same way, by chain termination.

Exactly the same principle.

They lack that critical three -prime hydroxyl group.

When the viral reverse transcriptase enzyme tries to build the viral DNA chain, it grabs one of these NRTIs, like zetavudine or tenofovir, and click.

Chain stops.

It cannot be completed.

The virus cannot write its code into DNA.

The text lists a whole bunch of drugs here.

Zetavudine, which is AZT,

lamifudine, nebacavir, tenofovir, emtricidabine.

Do we need to know all of them?

You should definitely know the patterns.

Zetavudine, or AZT, was the very first one.

It's historically huge, especially for preventing mother -to -child transmission.

But it comes with a lot of toxic baggage.

And the modern ones.

Tenofovir and emtricidabine are the modern workhorses.

They're very often combined in a single pill, like Travada.

They are potent and much better tolerated.

And then you have abacavir, which is unique because of the hypersensitivity issue.

Right.

The text mentions a genetic test you have to do before prescribing it.

You absolutely must.

It's for a gene allele called HLAB57ZU1.

If a patient has this specific gene and you give them abacavir, they can have a massive systemic and potentially fatal allergic reaction.

So you screen every single patient before they ever get one dose.

What about general side effects for this whole NRTI class?

Table 43 .4 in the book has a big warning about mitochondrial toxicity.

Yeah, this is a fascinating and unfortunate bit of pharmacology.

Remember, mitochondria, the little power plants inside our cells, are thought to have evolved from ancient bacteria.

They have their own DNA and their own DNA polymerase called polymerase gamma.

And the NRTIs can hit that polymerase too.

Unfortunately, yes.

They can sometimes fool our mitochondrial polymerase gamma, not just the virus's reverse transcriptase.

So we inhibit the virus, but we also accidentally poison our own mitochondrial.

And when your mitochondria start to fail, what does that look like?

It's not good.

You get lactic acidosis, which is a dangerous buildup of acid in the blood.

You get hepatic steatosis or fatty liver, and you can get peripheral neuropathy.

It's much less common with the newer drugs like penifovir, but it was a major, major issue with the older ones like AZT and stavidine.

Okay, let's move to class two.

NNRTIs, the non -nucleoside reverse transcriptase inhibitors.

The non is the absolute key here.

These are not fake bricks.

They do not look like DNA building blocks at all.

They are not competitive inhibitors.

So how do they work then?

Think of them as sand in the gears.

They bind to a completely different spot on the reverse transcriptase enzyme, a little pocket far from the active site.

It's called an allosteric site.

By binding there, they cause the whole enzyme to twist and change its shape.

So it locks the enzyme up.

It locks it up so it can't do its job anymore.

It's like jamming a wrench into the machinery.

The drugs here are efavirenz, nevirapine, rilpivirine.

Right.

Efavirenz is the classic one to know for exams.

It's potent, it's effective, but it has very distinct side effects.

The text makes a big point about its CNS toxicity.

What does that mean for the patient?

It can cause dizziness, insomnia, and these incredibly vivid, often disturbing dreams or nightmares.

There are also neuropsychiatric effects like depression.

And there's a pregnancy warning too, right?

Efavirenz is teratogenic, especially in the first trimester.

It can cause neural tube defects.

So we avoid it in women who are pregnant or might become pregnant.

Okay, on to class three, protease inhibitors, the scissors jammers.

This class targets the very last step of the life cycle.

Remember how we said HIV makes its proteins as one giant useless rope called a polyprotein?

Right.

Well, it needs the HIV protease enzyme to act like a pair of scissors and snip that rope into all the functional parts.

It's like cutting a sheet of stamps into individual stamps so you can use them.

And protease inhibitors stop the sniffing.

They jam the scissors.

They're designed to fit perfectly into the active site of the protease enzyme, blocking it.

The result is that the new virus particles bud off the cell, but they are immature.

They're full of uncut junk protein.

They can't go on to infect a new cell.

The naming convention here is a gift to students.

They all end in navir.

Retonavir, adizanavir, darunavir.

It's a helpful trick.

Now, retonavir is a special case.

The text calls it a pharmacokinetic booster.

Don't really use it for its antiviral effect anymore.

Not at its full dose, no.

We use it to game the liver.

Retonavir is an incredibly potent inhibitor of a liver enzyme called CYP3A4, which is the main enzyme that metabolizes most other drugs.

You use it to make the other drugs stronger.

Exactly.

Imagine you're taking another protease inhibitor, like darunavir.

Normally, your liver would see that darunavir and start chewing it up and clearing it from your body pretty quickly.

But if we add a tiny baby dose of retonavir to the regimen, it shuts down the liver enzyme.

It completely shuts down the CYP3A4 drug disposal system.

So now the darunavir levels stay high and steady in the blood for a much longer time.

It boosts the other drugs.

So tonavir is like the bodyguard that distracts the bouncer so the main drug can stay in the club all night.

That is a perfect analogy, yes.

But the side effects of the protease inhibitors as a class,

the text uses the term metabolic syndrome.

That sounds bad.

It is the great tragedy of long -term HIV survival.

These drugs save your life, but over years they can really change your body.

They cause a condition called lipodystrophy, which is a bizarre redistribution of body fat.

Patients lose fat in their face and limbs, so their cheeks look sunken and veins pop out, and they gain fat centrally in the abdomen and on the back of the neck, which is often called a buffalo hump.

And that's not all, is it?

No.

It also drives up cholesterol and triglycerides and causes insulin resistance.

It basically gives the patient a syndrome that looks a lot like type 2 diabetes and heart disease waiting to happen.

Which brings us to class 4.

And the transfer inhibitors or NSTIs?

They absolutely are.

Raltogravir, dilugravir, bictagravir.

These drugs inhibit that critical step of pasting the viral DNA into the human chromosome.

And they're preferred now because they're better tolerated.

Much better.

They are incredibly potent, have a high barrier to resistance, and generally, they don't cause that awful metabolic nastiness that we see with the protease inhibitors.

They are the backbone of most modern first -line therapy.

Okay.

And finally, there are the entry inhibitors, the drugs that stop the virus at the front door.

Right.

There are a couple of these.

We have Mariviroc.

It works by blocking that CCR5 co -receptor on the human cell.

It's like putting chewing gum in the keyhole so the virus can't unlock the door.

But there's a catch, isn't there?

There is.

You have to do a test first, called a tropism assay.

Some strains of HIV don't use the CCR5 keyhole.

They use a different one called CXCR4.

If the patient's virus uses CXCR4, Mariviroc is completely useless.

So it's a bit of a niche drug.

And the other one is Enfuvartide.

Enfuvartide is a fusion inhibitor.

It's a peptide, which is like a small piece of a protein.

And because it's a protein, you can't swallow it as a pill.

Your stomach would just digest it.

So how do you take it?

You have to inject it subcutaneously, twice a day.

And the injections hurt.

They cause painful nodules and reactions at the injection site.

Honestly, nobody wants to be on Enfuvartide unless they have run out of all other options due to resistance.

So putting it all together for the student trying to learn this, Table 43 .3 outlines the strategy.

What's the standard cocktail today?

The standard preferred regimen is usually two NRTIs.

The classic backbone is Tenofovir plus Amtricitabine plus Les West, one integrase inhibitor, like Belutagravir or Bictagravir.

So that's three drugs hitting at least two different steps in the life cycle.

Correct.

High potency, high barrier to resistance.

And thanks to modern pharmaceutical formulation, that entire three -drug cocktail can now be contained in one single pill taken just once a day.

That progress is just astounding.

From 20 pills a day with horrible toxicity to one pill a day.

Okay, let's leave HIV and talk about something a little more seasonal.

Influenza.

The flu.

An RNA virus, but a much, much simpler beast than HIV.

The main drugs the chapter focuses on are the neuraminidase inhibitors.

Osultamivir, which is Tomoflu, and Xanamivir.

We're gonna need another analogy.

What is neuraminidase doing?

Okay, so imagine the flu virus has finished replicating inside one of your respiratory cells.

It pushes out against the cell membrane to leave and go find a new cell to infect.

Right.

But the surface of our cells is covered in these sticky sugar molecules called sialic acid.

The brand new virus gets stuck to the sialic acid like a piece of Velcro.

It's tethered to the cell it just came from.

So it's all dressed up and ready to go, but its coat is caught in the door.

That's a great way to put it.

Neuraminidase is an enzyme that the virus carries with it that acts like a machete.

It floats over and chops the sialic acid tether, freeing the new virus to float away and infect its neighbor.

So Osultamivir, or Tamiflu, inhibits the machete.

It jams the machete.

The machete can't cut the tethers, so all the newly made viruses stay stuck to the surface of the dying cell.

They clump up, they can't spread, and the infection is contained much more effectively by your immune system.

But the text is very, very strict about the 48 -hour window.

Why is timing so critical here?

This is crucial for people to understand.

Flee replication peaks very, very early in the infection, often before you even feel that terrible.

If you wait until day three when you're miserable, the virus has already replicated billions of times, spread all through your lungs, and done most of its damage.

Blocking its release at that point is like closing the barn door after the course has already bolted.

So it only really works if you catch it immediately.

And even then, what's the actual benefit?

The data shows a reduction in the duration of symptoms by about one to one and a half days.

That seems pretty modest.

It is.

For a healthy young person, it's arguably not worth the cost and potential side effects.

But for an elderly resident in a nursing home, that one day less of high -level viral replication might be the difference between getting better and developing a deadly secondary bacterial pneumonia.

Now, oseltamivir is a pill.

Xanamivir is an inhaled powder.

Why does the text specifically warn about using xanamivir in patients with asthma?

Because inhaling any dry powder can be an irritant to the airways.

In someone with hyperreactive airways like an asthma or COPD, it can trigger bronchospasm.

You can actually induce an asthma attack while trying to treat their flu, so it's contraindicated in those patients.

The text also mentions a newer drug, biloxavir.

This one's different.

It is.

Biloxavir marboxyl.

It hits a completely different target, an enzyme called the cap -dependent endonuclease.

And in plain English, that means?

The flu virus is clever.

To make its own proteins, it needs to steal the cap from the beginning of our own messenger RNA.

Biloxavir stops that cap -snatching process.

It basically unplugs the viral photocopier before it can even make its first copy.

And the benefit of that one?

It's a single dose.

One pill and you're done.

Which is great for compliance.

And just for the history books, amantadine or remantadine?

The dinosaurs of flu therapy.

They used to block a thing called the M2 proton channel, which prevented the virus from encoding itself once it got inside the cell.

But the flu virus mutated around them decades ago.

Resistance is now near 100%.

We don't use them for flu anymore.

They're just a footnote in the textbook.

Alright, let's travel from the lungs to the liver.

Hepatitis.

Specifically Hepatitis B and C.

Right.

Two viruses that attack the same organ, but they require totally different pharmacological philosophies.

Let's start with Hepatitis B or HBV.

Hep B is a DNA virus.

And like HIV, it has a trick where it can integrate its DNA into the host genome in a way that makes it very, very difficult to completely eradicate.

It can hide out.

So the goal of therapy isn't necessarily a cure.

Not usually, no.

The goal is suppression.

We want to keep the viral load suppressed to undetectable levels for the long term so that the liver doesn't stay inflamed.

To prevent the long -term consequences.

Exactly.

We want to prevent the progression to cirrhosis, and most importantly, liver cancer or hepatocellular carcinoma.

And interestingly, the drugs we use for it are basically recycled from the HIV shelf.

Tenofovir makes another appearance.

Tenofovir and another drug called Enticavir.

They're both nucleoside or nucleotide analogs that inhibit the HBV polymerase, which also has reverse transcriptase activity.

Since this is long -term, maybe lifelong therapy, we need drugs with a very high barrier to resistance.

And these two are the champions.

Okay.

Now for Hepatitis C, HCV.

This is the section of the chapter that reads like a victory lap for science.

It absolutely is.

I mean, just a decade or so ago, treatment was an absolute nightmare.

Now it is a cure.

And I mean, a literal cure.

We can completely eradicate the virus from the body.

And we do that with the direct acting antivirals, or DAAs.

The names are a mouthful, but the text gives us a handy decoder ring.

Yes.

The suffix of the drug name tells you its mechanism.

This is super high yield for any student listening.

First, you have the drugs that end in prevavir.

Simaprevir, grazoprevir, glycoprevir.

So P -R -E -V -I -R for protease inhibitor.

You got it.

They inhibit the NS34A protease.

Just like with HIV, they stop the virus from cutting its polyprotein into functional pieces.

Okay.

What's next?

Second, we have the drugs that end in hasvir, ledipasvir,

velpotasvir, elbasvir.

Albasvir.

Let me guess A for NS5A.

Exactly.

NS5A is a critical phosphor protein that's involved in both viral replication and assembly.

If you inhibit it, you completely scramble the assembly line.

And the third group.

The third group ends in buvir.

So fosbuvir is the big one here.

Dossabuvir is another.

Real buvir.

So B for NS5B.

Perfect.

NS5B is the RNA -dependent RNA polymerase itself.

It's the copy machine.

So we have drugs that block the protease, provir, the assembly in the plant, and the polymerase buvir.

And just like with HIV, we combine them.

Always.

You never, ever use monotherapy.

You might combine a guvivir with an hasvir, for example.

The brand name EPCLUSA is sofasbuvir plus velpotasvir.

And the results.

The results are stunning.

These combination therapies have cure rates, what we call a sustained virologic response, or SVR, of over 95%.

And they do it in 8 to 12 weeks with very few side effects.

It's a miracle.

It sounds perfect.

Is there any catch at all?

Well, cost has been a major issue, though that's more of an economic discussion.

Pharmacologically, the text points out a very important drug interaction to be aware of, specifically with amiodarone.

The antiarrhythmic drug for the heart.

Right.

If you give a patient a regimen -containing sofasbuvir while they are also on amiodarone, you can get severe, life -threatening, symptomatic bradycardia.

The heart rate can slow way, way down.

We don't know the exact mechanism, but it is a major contraindication.

And just to appreciate how good these new drugs are, we should probably look at what we used to do.

The old -school treatment.

The dark ages.

We used a combination of interferon alpha and ribavirin.

Let's talk about interferon.

It's a natural substance our body makes, right?

It is.

Interferons are cytokines.

They're basically distress signals that an infected cell releases to scream to the immune system, hey, we are under attack over here.

So when we injected massive doses of synthetic interferon into patients, we were essentially chemically inducing a massive systemic flu -like state that lasted for months.

So the side effects were literally feeling horribly sick all the time.

Horribly sick.

Fever, chills, muscle aches, bone pain, but also severe neuropsychiatric effects.

Depression, anxiety, suicidal ideation.

Patients routinely described it as the worst year of that entire lives.

And after all that, it only worked maybe 50 % of the time.

And what about ribavirin?

Ribavirin is a broad -spectrum guanosine analog.

Its two main poxicities are, one, hemolytic anemia.

It literally makes your red blood cells burst.

And two, it is a potent teratogen.

It causes severe birth defects.

And it stays in the body for months after you stop taking it.

So men and women had to be on strict birth control for six months after finishing therapy.

Wow.

So replacing that whole ordeal with a pill a day for 12 weeks is, it's unbelievable.

It's one of the true miracles of modern pharmacology.

We are definitely in the home stretch now.

The text has a final grab bag section of other viral infections.

Let's just hit the highlights.

RSV.

Respiratory syncytial virus.

A major cause of bronchiolitis and pneumonia in young infants.

The main drug here is palivizumab.

And you should notice the unumab at the end of the name.

Monoclonal antibody.

Exactly.

It's a lab -made antibody that binds to the fusion protein on the surface of the virus, preventing it from entering cells.

But here is the key distinction.

It is prophylaxis.

It is not a treatment for a kid who is already sick.

It's a preventative measure.

Right.

It's given as a monthly shot to very high risk infants like very premature babies or babies with severe heart disease during the winter RSV season to prevent them from getting sick in the first place.

Okay, smallpox.

Theoretically eradicated from the world.

But because of fears it could be used as a bioweapon, we developed a drug called ticovirumat.

It inhibits a protein called VP37, which traps the virus inside the cell so it can't spread.

It's stockpiled by governments just in case.

And finally, the text addresses SARS -CoV -2.

And given the publication date of this edition, this is really a snapshot of the early pandemic era.

It's fascinating to see it in print, frozen in time.

It discusses hydroxychloroquine, the anti -malarial drug.

It notes that while it showed some activity in a petri dish and vitro, the clinical trials in actual humans showed no benefit and potential for harm.

It's a classic lesson.

A human being is not just a big petri dish.

It also mentions remdesivir.

Yes.

It's an adenosine analog that targets the viral RNA polymerase.

It causes premature termination of the RNA chain, kind of like our other chain terminators.

It was the first drug to get emergency use authorization and then full FDA approval for treating COVID -19.

And last, dexamethasone.

This one is critically important to understand.

Dexamethasone is a corticosteroid.

It is not an antiviral.

It does nothing to the virus itself.

It suppresses the immune system.

So why use it?

Because in severe COVID, it often wasn't the virus directly killing the patient.

It was the patient's own immune system going into overdrive, the so -called cytokine storm.

Dexamethasone calms that storm down.

It treats the over -exuberant host response, not the virus.

Wow.

We have covered a massive amount of ground here.

From the incredible precision of the kinase trick of a cyclover to the trojan horses of HIV, the machete jammer for Tamiflu, and the straight -up cure for hep C.

If you step back and look at the whole picture, the one single theme that runs through all of it is specificity.

Selective toxicity.

Finding that one little difference.

Exactly.

Viruses are the ultimate parasites.

They weave themselves so tightly into the fabric of our own biology.

The entire history of antiviral drug development is the history of brilliant scientists finding the tiniest, most subtle molecular differences.

A sloppy kinase, a unique protease, a sticky surface protein, and then exploiting those differences to save the host.

Yeah.

And I guess that brings us back to that very first thought from the beginning of the chapter.

Are they alive?

You know, when you see how they relentlessly mutate to evade a drug like AZT, or how they cleverly scavenge enzymes from the host cell, or how they literally write themselves into our DNA to hide.

It sure feels like life.

If it isn't life, it is certainly the most desperate, relentless, and powerful drive for survival you can imagine.

And that is what makes them such formidable opponents for pharmacologists to this day.

A provocative thought to end on.

And that is a wrap for this last minute lecture.

Deep dive into chapter 43.

Good luck on the exam.

I know it's a lot, but you've got this.

Thanks for listening.

We will see you next time on the deep dive.