5 ms·

Here's a summary including the mechanism of action from a UW professor in 2022: https://www.youtube.com/watch?v=9IbzMbfEMIY https://www.youtube.com/watch?v=9Ib

by w10-1 2y ago

Here's a summary including the mechanism of action from a UW professor in 2022: https://www.youtube.com/watch?v=9IbzMbfEMIY https://www.youtube.com/watch?v=9IbzMbfEMIY

hilbert42 2y ago
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?
- jaggederest 2y ago
  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.
  - hilbert42 2y ago
    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.
- mensetmanusman 2y ago
  The drug is a PFAS (as nearly half of new drugs are), so it can act that way in the body.
  - FooBarWidget 2y ago
    I thought PFAS are toxic?
    - amarant 2y ago
      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.
    - vasco 2y ago
      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.
    - PetitPrince 2y ago
      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.
      - Twisol 2y ago
        > 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 :(
        PetitPrince 2y ago
        Ah sorry, my French bias is shining through. I meant "canine tooth" (also known as a fang), not the Canis genus.
- refurb 2y ago
  > 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.
- 14 2y ago
  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.
  - supertofu 2y ago
    For someone with bone loss, isn't the long half life a good thing?
    - loa_in_ 2y ago
      It is. It's also very impressive for a medicine to exhibit such a long half life.
  - hilbert42 2y ago
    "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.
- suchire 2y ago
  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 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.
rlad 2y ago
No problem with this is it it does not interfere with infection. Only with replication. So it will not stop people from becoming infected.
- sddsdd 2y ago
  It does in fact prevent infection you have misunderstood. It very clearly prevents infection incredibly well, proof of that in the real world is exactly why there is excitement over this drug. It also sounds as though you misunderstood the mechanism, it interferes in both an early and a late step in the viral process, there no theoretical reason to describe it as "not interfering with infection".
  - rlad 2y ago
    From what I read, it interferes with capsid formation. Since HIV is a retrovirus, by the time capsid formation is happening it has already integrated itself with the host cell’s DNA. That implies that as long as the drug is present, the virus won’t be able to replicate, however as soon as the drug is no longer present the virus will start replicating. Because the cell has been infected.
- scotty79 2y ago
  There's no infection without replication.
  - sixfiveotwo 2y ago
    Of course, the illness cannot get worse without the virus first infecting a cell, and then replicating in that cell to infect other cells in the body, and then potentially infecting other hosts; that is how a virus works, right? Now, if replication is stopped, AND the body is able to destroy the first infected cell, then the patient is cured, but otherwise? I guess that even if the body's immune system cannot get rid of that "patient cell zero", it is quite possible that a 6 month period is enough for the cell to die from the virus. I do not have any medical training though, so please correct me if I am wrong.

by w10-1 2y ago

Here's a summary including the mechanism of action from a UW professor in 2022: https://www.youtube.com/watch?v=9IbzMbfEMIY https://www.youtube.com/watch?v=9IbzMbfEMIY

hilbert42 2y ago

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?

jaggederest 2y ago
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.
- hilbert42 2y ago
  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.
mensetmanusman 2y ago
The drug is a PFAS (as nearly half of new drugs are), so it can act that way in the body.
- FooBarWidget 2y ago
  I thought PFAS are toxic?
  - amarant 2y ago
    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.
  - vasco 2y ago
    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.
  - PetitPrince 2y ago
    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.
    - Twisol 2y ago
      > 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 :(
      - PetitPrince 2y ago
        Ah sorry, my French bias is shining through. I meant "canine tooth" (also known as a fang), not the Canis genus.
refurb 2y ago
> 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.
14 2y ago
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.
- supertofu 2y ago
  For someone with bone loss, isn't the long half life a good thing?
  - loa_in_ 2y ago
    It is. It's also very impressive for a medicine to exhibit such a long half life.
- hilbert42 2y ago
  "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.
suchire 2y ago
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 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.

rlad 2y ago

No problem with this is it it does not interfere with infection. Only with replication. So it will not stop people from becoming infected.

sddsdd 2y ago
It does in fact prevent infection you have misunderstood. It very clearly prevents infection incredibly well, proof of that in the real world is exactly why there is excitement over this drug. It also sounds as though you misunderstood the mechanism, it interferes in both an early and a late step in the viral process, there no theoretical reason to describe it as "not interfering with infection".
- rlad 2y ago
  From what I read, it interferes with capsid formation. Since HIV is a retrovirus, by the time capsid formation is happening it has already integrated itself with the host cell’s DNA. That implies that as long as the drug is present, the virus won’t be able to replicate, however as soon as the drug is no longer present the virus will start replicating. Because the cell has been infected.
scotty79 2y ago
There's no infection without replication.
- sixfiveotwo 2y ago
  Of course, the illness cannot get worse without the virus first infecting a cell, and then replicating in that cell to infect other cells in the body, and then potentially infecting other hosts; that is how a virus works, right? Now, if replication is stopped, AND the body is able to destroy the first infected cell, then the patient is cured, but otherwise? I guess that even if the body's immune system cannot get rid of that "patient cell zero", it is quite possible that a 6 month period is enough for the cell to die from the virus. I do not have any medical training though, so please correct me if I am wrong.