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Targeted steroids

Steroids that don't cause Cushings.
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I am fully aware that this idea has something of a vibe of a certain other user's ideas. Where is he incidentally? Haven't heard from him in ages.

Steroid receptors are inside cells on the nuclear membrane if I recall correctly. However, when people are given steroids for various conditions, their whole bodies are given them, so they can get side effects. This is unfortunate, since the action itself only needs to be in a few tissues.

Clearly they pass through cell membranes into the internal environment of the cell before reaching the nucleus. In that environment, there will be certain enzymes which will act upon particular compounds, such as yanking other groups off steroid molecules, and will not be present outside the cell, or at least will be less concentrated.

Consequently, it seems to me that if you added something to the steroid molecule which made it less active but still able to pass through the cell membrane, which could then be removed from the molecule once it was inside the cell, you would be able to target the steroid to the tissue it needed to be in. This is all very vague, but say you have a cell which makes keratin in the skin. That cell will be doing something enzymy to amino acids to make them into keratin for the epidermis. If that enzymy thing could be done to an extra bit tagged onto a steroid molecule, that steroid could then get to eczema without influencing the rest of the body as much because that same bit would've stopped it being steroidy elsewhere in the body.

I feel like I've lost my marbles so this is probably nonsense, but is it?

nineteenthly, Apr 01 2016

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       A place to start is some sort of understanding about why existing corticosteroids differ in potency. I thought it was binding affinity but could it be lipophilicity?
bungston, Apr 01 2016
  

       //I feel like I've lost my marbles so this is probably nonsense, but is it?//   

       You've invented pro-drug pharmacology. This has, unfortunately, already been invented. Turns out it's quite tough.
bs0u0155, Apr 01 2016
  

       I'm aware of pro-drugs but I'm not aware that it's been applied to steroids.
nineteenthly, Apr 01 2016
  

       //Where is he incidentally?// If the person you're thinking about is the person I think you're thinking about then (rather worryingly) I think he tends to live outdoors these days - somewhere kind of Portland(ish). There are occasional YouTube uploads of snippets here and there, but I've not seen anything for maybe 6 months or so. I do hope they're OK. I have considered, in flights of fancy, that if I were ever over that way, I might try and look them up, but I'm not, and I'd probably be too embarrassed/shy/something-else and rationalise a reason not to if I ever were.
zen_tom, Apr 06 2016
  

       //pro-drugs but I'm not aware that it's been applied to steroids//   

       Prednisone is an example. Metabolized to prednisiolone in the liver. The liver is your best target for pro-drugs, it has by far the most unique enzymes of any tissue.   

       I should explain my point about your idea better. You gave the example of the skin. Now, it's true that there are a train of enzymes used in in the synthesis of keratin. We don't seem to know much about them, there's 30-ish keratins in skin cells, but then there's a whole lot of interrelation between that and the cytoskeletal proteins used in all sorts of cells. Essentially, it' a massive mess. Your strategy would need you to find a catalytic enzyme which is unique to your tissue of interest. If you could use one of them to activate a pro steroid, then great. But enzymes are relatively specific. If you have an enzyme that's involved in keratin synthesis, then you need to design your pro-drug to interact with that. But it probably won't, because steroids aren't shaped like keratin.   

       Imagine you solve that problem, and you have a good skin-specific candidate enzyme which cleaves a group off a steroid pro drug leaving the active derivative. Say it's cortisone. Now your drug diffuses out and you barely achieve any specificity at all. So you design a cortisone derivative that is functional, but not cell permeable. This is tricky, this ISN'T cortisone. So now you're in the novel pharmaceuticals game: you multiply your problem by the existing problems faced by the pharma industry.   

       1. is it toxic? We know the steroid isn't, but what about the pro-drug? or the non-permeable derivative?   

       2. is it available? curcumin is quite good at killing pancreatic cancer cells. Great, we should all eat a ton of turmeric to head pancreatic cancer off at the pass. Except that it's not absorbed. It's a fun way to get fluorescent poo however.   

       3. is it active? too active? not active enough? Does it build up? Does it absorb UV?   

       And so on. One of the biggest problems is beating existing drugs. You have to prove it's better, and it's hard to get better targeting, for the skin at least, than just rubbing it on.
bs0u0155, Apr 06 2016
  

       We never really answered [nineteenthly]'s question of whether or not he's lost his marbles.
MaxwellBuchanan, Apr 06 2016
  

       Does anyone know where thery are now ? if so, technically they're not lost.   

       // it's hard to get better targeting, for the skin at least, than just rubbing it on. //   

       12-bore shotgun ?
8th of 7, Apr 06 2016
  
      
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