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Comment by hilbert42 | Hacker News Reader

Not my field so please bear with me. Before watching the video the notion of interfering with the capsid as a mechanism for stopping the virus made sense.

However, what I still don't have a handle on is how does lenacapavir act so long that it only needs to be administered every six months?

From the explanation lenacapavir works on the capsid directly, it's not acting on the immune system by training the body's defences as with a traditional vaccine. Surely this molecule can't just hang around for six months without being gobbled up by the liver or such.

What am I missing here?

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It's got so many fluorines running around that intuitively as an amateur chemist I would expect it to have an extraordinarily long half life in the human body, especially so if it's administered as a depot injection in something with a large molecular weight. It takes your body a long time to chew through the inactive components in a depot injection.

Yeah, I also noted the fluorines (and Lowe's comment), and I know they're used to prolong action such as with, say, fluoxetine with its three fluorines but six months seems extremely long. I'd have thought it'd have been flushed out long before that. Presumably, it must bind to lipids, fats etc.

Anyway, whatever, it's clearly a brilliant bit of chem eng.

> Surely this molecule can't just hang around for six months without being gobbled up by the liver or such.

It can! The fluorines likely protect the metabolic target. At that point you're relying on excretion of unchanged drug through the kidneys or liver (which excrete into bile, and then eliminated in feces).

Google tells me the half-life of the subcutaneous administration is 2 to 3 months, so twice yearly injections makes sense.

I would have thought that too but at one point I had clients taking a bone loss drug called Alendronate. Looking up the drug I was shocked to see that it has a 10 year half life in bone tissue. So yes some drugs once taken will stay in certain tissues for a very long time.

For someone with bone loss, isn't the long half life a good thing?

It is. It's also very impressive for a medicine to exhibit such a long half life.

"I was shocked to see that it has a 10 year half life in bone tissue."

Well so am I. One of the great things about HN is the sheer amount of stuff I learn from others who post here. Alendronate is yet another instance. :-)

As Alendronate, Alendronic acid, is not a drug I'm familiar with I've just looked it and its structure up on Wiki to get a rough idea what it's about.

I'm not doubting Alendronic acid's 10 year half life in bone tissue but I'm now curious how that comes about. It has five hydroxy groups which I'd have thought would have made it highly soluble in water. And —OH groups tend to be reactive.

As I said, biochemistry isn't my field but I'm now intrigued about how it actually works. No doubt the phosphorus bonds to or goes into strengthening bones but why that doesn't happen immediately has me stumped. So experts I need your help.

Clearly, many chemicals can and do survive in tissue for years, PFAS being an example but we don't think of them being highly reactive either. Obvious examples of chemicals that aren't eliminated by the body that everyone is familiar with are tattoo dyes. No doubt a bad example as they don't seem to be biologically active and remain more by mechanical adhesion than by any other means.

The issue I don't have a good handle on is how biologically active drugs can remain unchanged for so long before being taken up and used by the body. Perhaps they're stored as intermediate metabolites or similar.

The drug is a PFAS (as nearly half of new drugs are), so it can act that way in the body.

I thought PFAS are toxic?

It's somewhat unclear, but given that they've been found in every piece of human tissue tested for it, I'd say at the very least it kills slower than HIV. Of course there are many different kinds of PFAS, some might be worse than others.

Most vaccines have had some toxic component in them particularly historicaly. If you look up different vaccine types over the past 50 years you'll see often ingredients are removed or replaced because of it. The general wisdom is that it's either small enough quantities that you'd have less negatives from the toxicity than you have from being able to prevent the disease at a population level.

PFAS only describe one part of the overall molecule. It doesn't necessarily tells if the rest of the structure is toxic or not. It's like saying "I though canine were dangerous?" (yes for big cats, no so much for your average French bulldog).

Also, the dose makes the poison, etc.

> It's like saying "I though canine were dangerous?" (yes for big cats, no so much for your average French bulldog).

Big cats are not canines :(

Cats, big as well as small, are feline :)

Ah sorry, my French bias is shining through. I meant "canine tooth" (also known as a fang), not the Canis genus.

Ah, that totally makes sense! No worries :)

‘PFAS toxic’ is about as sophisticated as saying ‘Nuclear bad’.

Western society isn’t scientifically literate enough to develop these things at the moment, so they will happen in APEC for now.

No. The drug is not a PFAS.

PFAS stands for a very specific thing: perfluorinated alkenes. The drugs in question are not alkenes.

Damn it, autocomplete. Alk_a_nes, not alkenes.

This is a paper describing the pharmacokinetics (the rates of various phases of entering the blood and clearing out of the body) for various formulations of the drug, and their hypotheses for why this might be the case:

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.3c00626

tl;dr: the molecule is poorly soluble in water, so by suspending a bunch of microparticles and injecting them subcutaneously, the drug very slowly dissolves over time, and it’s very potent, so only a little bit is necessary to do its job.

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