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Past the Limits

Michael Gilman has an interesting article up at LinkedIn about trying to get past the current small-molecule limits of medicinal chemistry. His suggestion is “Why not RNA?”

This is not entirely crazy. Many approved antibiotics act by binding to ribosomal RNA. And Novartis’s fascinating splice-corrector LMI070, which is in clinical trials for spinal muscular atrophy, appears to act by binding specifically to the errant splice site in SMN2 pre-mRNA and stabilizing its interaction with the U1 snRNP. LMI070 is a pleasingly conventional small molecule that a non-chemist like me would not be blamed for confusing with a kinase inhibitor. Importantly, it is orally bioavailable and penetrates the blood-brain barrier. It’s proven safe enough to enter clinical development, suggesting it’s unlikely to be a pleiotropic RNA binder. Consider, too, ribocil, a very ordinary-looking molecule that Merck identified in a phenotypic screen in E. coli. It turns out to act by binding to a riboswitch, a ligand-regulated RNA structure found in the 5’-untranslated regions of certain bacterial mRNAs.

He’s got a point. I know that there have been some screens run out there, but these examples hint that there may be a lot more to be found. The promise of RNA interference and other approaches that use modified oligonucleotides has taken up a lot of the effort in this area, but small molecules probably deserve more of a shake than they’ve gotten.

I’ve had similar thoughts, though, about some other classes of biomolecules over the years. Complex carbohydrates would be another pick in the “almost completely underexploited” section, but that’s partly because the biology is such a tangle. In fact, I’d nominate them for underexploitation across the board, because polysaccharides are a lot more important than you’d think, compared to their profile in the literature (outside of perhaps immunology). That goes for cell surfaces and individual protein modification, and it goes for small molecule natural products as well. Think of the many that have odd little modified sugars hanging off them – they’re necessary for activity, in most cases, but they don’t get much respect, thus the syntheses of “Whatevermycin aglycon”. I’m not sure if I’ve ever seen a small molecule that recognizes some carbohydrate motif, and that’s probably because you almost never see anyone screening for one. Here’s a paper on the idea, and here’s a challenge from Novo Nordisk (which they have since withdrawn) to find a small-molecule glucose binder.

Lipids have come up in the context around here, too, and are starting to get more attention. There are deficiencies on the biology side here, too – if all the controversy about human dietary recommendations over the years teaches us anything, it’s that our knowledge of lipidology is completely inadequate. I got that impression when I dug into it about fifteen years ago, and nothing I’ve seen since then has changed my mind. Our biochemistry is capable of distinguishing very subtle differences in some very long and greasy molecules, and we really don’t know what’s going on yet. There are lipid-handling enzyme targets out there that have been addressed, but I’ve yet to see a pure lipid-interaction target (or screen), as far as I know. The chemical matter coming out of something like that would likely be challenging to work with, but I’d like to see some.

25 comments on “Past the Limits”

  1. Dr CNS says:

    Matt Disney at Scripps FL has been working on small molecules binding RNA for a while…
    https://disney.florida.scripps.edu/

    1. Derek Lowe says:

      Yep, one of those links is to a recent paper of his.

  2. luysii says:

    We’re so used to protein protein interactions in the cell that we no longer think of the individual proteins as ‘drugs’. Consider the naturally occurring serine protease inhibitors (serpins). The business end of each serpin is a 15 amino acid peptide on its surface. It interacts with active site of the serine protease, which cleaves it, causing a conformational change in the central beta sheet of the serpin. This is accompanied by a large increase in serpin stability, yielding a stable serpin/protease complex which is subsequently removed from the extracellular fluid.

    Is the 15 amino acid peptide a drug? is the whole protein? Could we make a large molecule drug like it for kinases ?

  3. Barry says:

    As to carbohydrates, small molecules targeting Sialyl LewisX were a hot topic for some years. They taught us a lot about inter-molecular interactions. Particularly, we learned that target-binding by H-bonds is often an enthalpic wash. The target and the drug spend as much energy to desolvate as you get back when they bind. And carbohydrate-like molecules tend to have very small Volumes of distribution.
    As to lipids as drugs, of course there are the prostaglandins which are (modified) lipids. And there’s a lot of literature on antagonists of Platelet
    Aggregation Factor (PAF) that certainly look like lipids (but never got through the clinic in my memory)

  4. Curious Wavefunction says:

    Have we figured out the “carbohydrate code” (whatever it may be) yet?

    1. luysii says:

      No, but an old friend from grad school (Sam Danishevsky) has been working on it for much of his career

    2. Old Timer says:

      Most people believe there is no “code,” just random glycosylation in the Golgi. I think there is a code and have designed experiments to get at it. But the uphill battle against “conventional wisdom” prevents this from getting off the ground with any practical amount of seed money. It’s too bad.

  5. mallam says:

    Yes, interesting idea. But there’s always a catch when it’s not being worked on….such as:
    delivery, delivery, delivery. How to get it to where it needs to be…..

  6. Ted says:

    I couldn’t agree more with the carbohydrate observations.

    This is still on the other side of the screen, but Carolyn Bertozzi presented research at the 2016 ACS in San Diego that demonstrated sialyl motifs could function as naturally selected ‘cloaking’ devices for solid tumors. They subsequently engineered mAb/enzyme fusions to recognize and cleave the sialyl residues, rendering the tumor cells ‘visible’ to natural killer T cells. Powerful, fundamental stuff here…

    -t

  7. Jack Straw from Wichita says:

    “complex carbohydrate synthesis”

    yuck

    1. Overthetop says:

      Having done my graduate work in this field…I’d say “yuck” might be too kind. Probably the biggest contributing factor to me no longer being in R&D…

  8. Kent G. Budge says:

    Lipid bilayers are made of long and greasy molecules. It seems to this non-biologist that it really should be no surprise that subtle differences between them makes a big difference in how a cell behaves.

  9. I’m an RNA (blocking, inhibiting..) fan! But it depends on the disease –

  10. Mach4 says:

    There are certain classes of molecules that act as spatial organizers of RNA and LMI070 is probably one of them. The tetracyclines also act in the same way, spatially organizing RNA and acting similarly in SMA, which nobody seems to understand although they have significant activity against the current SMA assays in vitro.

  11. Mark Thorson says:

    Let’s not forget that the intranasal route has somewhat similar bioavailability to intravenous, but it’s something you can do at home without a needle like oral. It has the further advantage of getting past the BBB. If someone comes up with an RNA or protein for an anti-Alzheimer’s therapeutic, this might be the way to deliver it. That’s been tried with insulin, but it looks like energy metabolism is not the problem in AD. Maybe some antibody or interference RNA for an enzyme in amyloid-beta or tau processing is in the future, as a daily intranasal dose. Maybe add a little cocaine to ensure patient compliance.

    Oh yeah, that was really good solanezumab.

    1. Lane Simonian says:

      The inadequate transport of glucose can be a problem as Alzheimer’s disease progresses, but too much insulin can be a problem at least during the early stages of Alzheimer’s disease.

      The role of RNA-protein binding in Alzheimer’s disease is perplexing at this point. The consequent formation of stress granules appears to be initially a neuroprotective response. Whether this ultimately fails or whether the stress granules eventually contribute to the progression of the disease is still an open question.

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256948/

  12. Barry says:

    way past the limits of normal small-molecule thinking you find natural products like streptomycin. It’s a complex saccharide that binds to RNA. Although it has zero oral bioavailability, it does get out of the plasma compartment well enough to be a useful antibiotic (its target is the bacterial ribosome, not something that’s plasma-exposed) when given i.m or i.v. And since it’s active against TB, it much be getting through mammalian cell membranes, too.

  13. Dependent says:

    @barry- most likely active transport

    1. Barry says:

      Because mycobacterium tuberculosis is an intracellular pathogen, streptomycin needs (active?) transport first through (at least one) mammalian cell membrane before it can get ported through the bacterial wall/membrane.
      Now that we’ve seen diffraction structures of antibiotics of a few classes bound to bacterial ribosomes, we can try rational modifications (or whole new structures) but engineering drug candidates to exploit active transporters still seems a daunting barrier.

  14. abc says:

    Fyi–for perspective chem grad students, do not join TSRI. It is a scam, and you will be abused, with your PhD results trasferred to Pfizer.

  15. gippgig says:

    “I’ve yet to see a pure lipid-interaction target”? Antifungal polyenes – selective ergosterol binders.

  16. rna guy says:

    Target abundance of proteins and RNA is very different; also keep in mind that 95% of cellular RNA are rRNA and tRNA, and these are the most ‘structured’ ones, the rest are quite unstructured or very dynamic. There are not many binding pockets to target.

  17. Grey Williams says:

    “There’s plenty of room at the bottom.”
    R. Feynman, RIP

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